SPORE in Leukemia

Principal investigator Daniel C. Link, MD, the Alan A. and Edith L. Wolff Professor of Medicine.


Principal Investigator: Daniel Link, MD

Washington University’s Specialized Programs of Research Excellence (SPORE) in Leukemia aims to develop novel biomarkers and treatments for leukemias and myelodysplastic syndromes. In this SPORE, we leverage our expertise in cancer genomics, immunology, and hematopoiesis to develop innovative translational research in leukemia.

Our SPORE includes four translational research projects:

Project 2- Targeted Therapies for T- ALL
  • Basic Science Co-Leader: Daniel Link, MD
  • Clinical Science Co-Leader: Geoffrey Uy, MD
Project 3- Novel Therapies for Spliceosomal– Mutant MDS
  • Basic Science Co-Leader: Matthew Walter, MD
  • Clinical Science Co-Leader: Timothy Graubert, MD
Project 5- Memory- like NK cell augmented hematopoietic cell transplantation for AML 
  • Basic Science Co-Leader: Todd Fehniger, MD, PhD
  • Clinical Science Co-Leader: Amanda Cashen, MD
Project 6- Chimeric antigen receptor T-cell therapy for T cell malignancies
  • Basic Science Co-Leader: John F. DiPersio, MD, PhD
  • Clinical Science Co-Leader: Armin Ghobadi, MD

These projects are supported by three shared resources: Core A. Biospecimen Processing; Core B. Biostatistics; and Core C. Administration. This SPORE also supports a Career Enhancement Program to recruit and mentor new investigators in translational leukemia research and a Developmental Research Program to support innovative translational concepts.

SPORE Shared Resources (Cores)

Core A: Biospecimen Processing

Director: Peter Westervelt, MD, PhD
Co-DirectorMark Watson, MD, PhD

The Biospecimen Processing Core (Core A) is responsible for the identification and enrollment of every patient referred to the Siteman Cancer Center with newly diagnosed and relapsed hematologic malignancy (excluding multiple myeloma). The pathologic material from these patients will be banked using the existing Siteman Cancer Center (SCC) Tissue Processing Core (TPC), and clinical data will be tracked prospectively in a clinical database.

Core B: Biostatistics

Director: J. Philip Miller, PhD

The Biostatistics Core provides resources to assist in the planning, conduct and analysis of the proposed research in such a way that quantitative analyses are appropriate and illuminating. The Core also assists in the dissemination of appropriate information both within and external to the SPORE and the Siteman Cancer Center (SCC). The Core is staffed by a dedicated biostatistician for each of the 4 projects. In addition a designated faculty member is devoted to collaborations concerning specialized bioinformatics issues. The Biostatistics Core will serve as a resource and collaborator for the four main projects proposed in this application, Career Development Program and Developmental Research Program projects and the SPORE Cores.

Core C: Administration

Director: Daniel Link, MD

The Administration Core provides executive oversight and administrative support for all of the projects and cores that comprise the Leukemia SPORE. The goal of the Administration Core is to monitor the activities of all of the program components, to comply with all local and federal guideline for grant administration, and to facilitate communication and collaboration among the program members.

Career Enhancement Program (CEP)

Matthew Walter, MD, Geoffrey Uy, MD, and Timothy Ley, MD

The goal is to recruit and support new independent investigators in the field of translational leukemia research. The research initiatives that will be funded by the CDP are expected to have a major translational component, focusing on leukemia etiology, diagnosis, early detection, treatment, or population science.


Junior faculty (Instructor or Assistant Professor) without RO1 or equivalent grant or senior post-doctoral fellows (PhD, MD, or MD-PhD) who have a written commitment from their department chair indicating promotion to Instructor or Assistant Professor by the time of the award also will be eligible.


One award of $70,000 (direct cost) will be made annually. The second year of funding is contingent upon adequate progress.

Submission Guidelines

The current application cycle is closed. For additional information please contact Michelle Callahan at [email protected].

2022 Awardees

Maggie FerrisMaggie Ferris, MD, PhD

Project Title: Defining the Interactome of RXRA in Leukemia

The objective of this study is to improve retinoid-targeted treatments for acute myeloid leukemia (AML) by evaluating and defining the molecular targets of retinoic X receptor alpha (RXRA). Our understanding of the biology of acute myeloid leukemia (AML) has expanded greatly in the past two decades, but 5-year survival remains at 29%; alternative, targeted, less toxic treatments must be developed. One subtype of AML, acute promyelocytic leukemia (APL), can be cured without standard chemotherapy by treatment with all-trans retinoic acid (ATRA) because the disease is initiated by fusion proteins of the retinoic acid receptor alpha (RARA); however, APL only accounts for ~15% of AML cases. ATRA has had more modest effects in non-APL AML trials, although subgroups of AML patients may be highly sensitive. RARA forms a heterodimer with RXRA to modulate gene expression when activated by retinoids. The targets of RARA:RXRA in leukemia are unknown but influence self-renewal and myeloid development. RARA and RXRA have augmented expression in leukemias driven by MLL translocations, and we have found this subtype is susceptible to retinoid combinations in vitro. MLL translocations are enriched among infant leukemia and have particularly poor outcomes. An improved understanding of retinoid biology will enable optimization of retinoids as a novel therapy for MLL-rearranged and infant leukemia.

Karolyn OetjenKarolyn Oetjen, MD, PhD

Project Title:  Stromal influence on malignant hematopoiesis in myeloproliferative neoplasms

Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) can result in profound architectural distortion of the bone marrow microenvironment and extramedullary hematopoiesis, most strikingly observed in myelofibrosis. Extensive reticulin fibrosis is a prominent morphologic feature, and reduced expression of key hematopoietic niche factors has also been recently suggested. The central hypothesis addressed in this research is that malignant hematopoietic cells in patients with MPN actively remodel the bone marrow microenvironment to promote clonal expansion, progression to myelofibrosis, and extramedullary hematopoiesis. Single cell RNA sequencing approaches have resolved the cellular heterogeneity of murine bone marrow stromal cells, with multiple studies of transgenically targeted mice contributing to an atlas of cell states. However, the topography of these stromal cell subsets in the bone marrow and their functions are not well understood. Furthermore, human counterparts to these cell types have not been defined and have unknown spatial distribution. This represents an important knowledge gap in the field that has limited our ability to characterize the impact of alterations in bone marrow stromal cells on hematopoiesis in MPN and other hematopoietic malignancies. To address this important knowledge gap, we developed an approach using fresh bone marrow biopsy samples and antibody-labeled single cell RNA sequencing (Cellular Indexing of Transcriptomes and Epitopes by Sequencing, CITE-Seq) to characterize human BM stromal cells from healthy donors. To fully characterize stromal cells, it is important to define their topography in the bone marrow; thus, we developed a multiplex imaging approach using in situ RNA hybridization to generate a spatial map of stromal cells in human bone marrow.

2021 Awardee

Dr. FerraroFrancesca Ferraro, MD, PhD

Project Title: The MYC protein interactome

The long-term goal of this study is to better understand the role of MYC mutations in the pathogenesis of AML, and to ultimately use this information to improve the therapy of AML. In this proposal, we will perform an unbiased screen to define the “MYC protein interactome” in acute myeloid leukemia (AML). Although MYC is a potent oncogene that has been associated with poor outcomes in patients with many solid tumors, its precise role in AML pathogenesis is still not clear, in part because it is over expressed in virtually all AML samples. In our recent clinical study of normal karyotype AML patients that achieve cure after receiving chemotherapy only as treatment, we found that MYC mutations were significantly enriched in these individuals (6/28 cases, compared to <2% of all AML cases, FDR=0.01). Consistent with these clinical observations, we have found that the MYCP59Q mutation – one of the most common found in AML – sensitizes cells to cytarabine in vitro and in vivo. Since MYC is a transcription factor, we performed single-cell RNA-seq (scRNA-seq) using murine hematopoietic cells expressing MYCWT or MYCP59Q, and found that expression of MYCP59Q alters the expression of a cohort of genes involved with RNA splicing. To begin to understand the molecular basis for these observations, we have evaluated how the P59Q mutation impacts MYC protein function, and have shown that the MYCP59Q significantly prolongs MYC half-life. Further, using an unbiased protein proximity-labeling assay (“Bio-ID”), we have found that the MYCP59Q protein alters the ability of MYC to interact with several transcriptional co-activators. Our preliminary results strongly suggest that mutations in MYC can lead to unique cellular consequences that differ from over expression of the wild-type MYC protein. Specifically, we hypothesize that AML-associated MYC mutations can alter its ability to bind co- activators or other relevant proteins, which may cause altered MYC target binding, causing transcriptional changes that sensitize AML cells to cytarabine. This proposal will expand on these observations to elucidate the functional and molecular consequences of AML-associated MYC mutations.

2020 Awardee

S Persaud

Stephen Persaud, MD, PhD

Project Title: Antibody-drug conjugates for chemotherapy and radiation-free HSCT conditioning

AML is a devastating malignancy with a 28% overall 5-year survival in adults, and alloHSCT provides the best chance for cure. The known anti-leukemia benefit of alloHSCT comes from two factors: pre- transplant conditioning with chemotherapy and/or radiation, and the graft-versus-leukemia (GvL) effect. However, a longstanding challenge is that these benefits are inextricably linked to two major risks to the patient: conditioning regimen-related toxicities and GvHD. The adverse effects of alloHSCT are poorly tolerated in elderly patients or patients with medical comorbidities, which is particularly problematic since AML is predominantly diagnosed in elderly adults and is more aggressive with advancing age. Thus, the patients whose disease warrants the most intensive therapy are often the least able to tolerate it. It is therefore an urgent, unmet clinical need to develop conditioning regimens that minimize treatment-related morbidity and mortality without losing the critical anti-leukemia benefit of alloHSCT.

The long-term goal of this proposal is to use targeted immunotherapeutics as the basis for novel, minimally toxic strategies for alloHSCT conditioning that do not require chemotherapy or radiation. Previously, ADCs composed of a CD45.2-specific antibody linked to the ribosome-inactivating protein saporin (CD45-SAP) were shown to permit high-level engraftment in murine syngeneic HSCT1. We extended these findings to the allogeneic setting, showing that CD45-SAP plus T cell depletion permitted stable engraftment in MHC-matched and F1-to-parent (haploidentical) HSCT. Further, the JAK1/2 inhibitor baricitinib, previously shown by our lab to potently inhibit GvHD, permitted short-term engraftment in F1-to-parent HSCT models when combined with CD45-SAP. Strikingly, CD45-SAP conditioned mice showed minimal morbidity or mortality in a parent-to-F1 GvHD model compared to mice conditioned with sublethal irradiation. Finally, human CD45-SAP successfully targeted human AML cell lines, primary AML cells, and cord blood-derived CD34+ cells in vitro. Based on these preliminary studies, we hypothesize that CD45-SAP-based conditioning can achieve the goals of alloHSCT – making room for donor HSCs, overcoming immune barriers to engraftment, and eliminating leukemia cells – without chemotherapy, radiation, or GvHD.

2019 Awardee

Miriam Kim, MD

Miriam Kim, MD

Project title: Chimeric antigen receptor T cells targeting KIT for treatment of acute myeloid leukemia

T cells can be genetically engineered to target a specific cell surface marker that is present on cancer cells, and this form of therapy, termed chimeric antigen receptor (CAR) T cells, has been highly successful in the treatment of acute lymphoblastic leukemia. We propose to adapt CAR T cell therapy to meet the unmet needs of patients with acute myeloid leukemia (AML), an aggressive disease with generally poor clinical outcomes. One of the barriers to utilizing CAR T cells for AML has been the concurrent presence of AML surface markers on normal blood stem cells, as targeting these antigens will then lead to bone marrow failure. Prior efforts in the field have concentrated on trying to find strategies to mitigate this toxic side effect; however, we propose to use this to our advantage, by developing CAR T cells as both a therapy for AML and a conditioning regimen prior to allogeneic hematopoietic stem cell transplant (HSCT). We believe that combining CAR T cells with an HSCT will maximize the benefit of both therapeutic approaches and can lead to long-term cures for patients with AML. As proof-of-concept for this strategy we plan to target KIT, a classical marker of HSPCs, with CAR T cells. We will extensively characterize the activity and toxicity of this therapy in different mouse models to ensure its safety and efficacy.

2017 Awardee

Matt Christopher, MD, PhD

Matthew Christopher, MD, PhD

Project title: Error-Corrected Sequencing for Early Detection of AML Relapse After Stem Cell Transplant

Acute Myeloid Leukemia (AML) is a life-threatening blood disease that affects about 20,000 new patients every year.  For many patients, the best chance for a cure is by getting a hematopoietic stem cell transplantation (HSCT) from a donor.  Unfortunately, many patients with AML—as many as 40-50%—still relapse even after transplantation, and the chances of curing patients in this setting are low. 

Most relapses after HSCT occur within the first two years, and patients undergo surveillance bone marrow biopsies at different time points during this period.  If there is evidence that patients are about to relapse, they can get some therapy to try to prevent the recurrence.  The methods for trying to predict relapse while the patient is still in remission are relatively insensitive, and it is possible that relapses could be treated more effectively if they are detected earlier.  For this reason, many researchers are trying to develop better techniques for predicting relapse.   In a preliminary study, our group showed that by using next-generation sequencing with deep coverage, some AML-associated mutations AML can be detected in remission samples up to six months before relapse.

In this proposal, we will go back to a larger group of patient samples and look for AML mutations in patients who ultimately relapsed as well as those who never relapsed.  We will test for the presence of mutations in the samples from relapse group and confirm that we can’t find mutations in the patients who didn’t relapse.  If successful, we will propose a clinical trial to test whether early prediction of AML relapse by mutation detection can predict and prevent relapse after HSCT.

2016 Awardee

Grazia Abou-Ezzi, PhD

Grazia Abou-Ezzi, PhD
Project title:  TGFB Signaling in Mesenchymal Stromal Cells

Hematopoietic stem/progenitor cells (HSPCs) reside in a specialized microenvironment within the bone marrow called the bone marrow niche. The bone marrow niche is a mix of multiple cell types, including mesenchymal stromal cells. In this study, we focus on understanding how the bone marrow niche is altered in mouse models of myeloproliferative neoplasms (MPNs).  Transforming growth factor beta (TGF-β) is known to regulate mesenchymal stromal cell differentiation; interestingly, TGF-β levels are significantly increased in MPN patients. We predict that TGF-β disturbs the bone marrow niche by altering mesenchymal stromal cell homeostasis and, furthermore, that this may lead to the splenomegaly observed in MPN patients. Recent data have shown that TGF-β is a major driver of bone marrow fibrosis. Although the cell of origin of bone marrow fibrosis is largely unknown, we predict that high levels of TGF-β stimulate the secretion of fibronectin and collagen by osteoblastic cells. 

To investigate Aim 1, we generated a mouse model in which TGF-β signaling is specifically suppressed in bone marrow mesenchymal cells. Using this model, we will characterize the role that bone marrow mesenchymal cells influenced by TGF-β signaling play in hematopoietic recovery following myelosuppression. In Aim 2, the MPL W515L retroviral transplant model will be used to induce bone marrow fibrosis. Transduced cells will be transplanted into the mouse model described in relation to Aim 1, followed by correlative analysis to assess changes in the bone marrow as fibrosis develops.

The ultimate goal of this study is to translate fundamental observations regarding TGF-β signaling effects on bone marrow mesenchymal cells and the hematopoietic compartment under myelosuppressive and myeloproliferative conditions into advancing care for patients with MPNs. We predict that the results of this study will improve the outcomes of these patients by providing critical insight into optimizing hematopoietic recovery after therapy with myelosuppressive agents. Furthermore, as there are currently no effective treatments for bone marrow fibrosis, our work may  provide the foundation for novel therapeutic strategies to treat bone marrow fibrosis in patients with MPNs.

Developmental Research Program (DRP)

Laura Schuettpelz, MD, and Daniel Link, MD

The goal is to support innovative translational leukemia research. Proposed projects will be reviewed with the intent that they will develop sufficiently, within one-two years, to be submitted for external peer-reviewed funding. For projects with a clinical trial, they must be ready to study activation within six months of award.


All faculty members (instructor level or higher) are eligible. In addition, senior post-doctoral fellows who have a written commitment from their department chair indicating promotion to Instructor or Assistant Professor by the time of the award will be eligible. Preference will be given to junior faculty or established investigators with a new translational leukemia research focus.


Up to three projects will be awarded a maximum of $70,000 (direct costs) on an annual basis. Selected projects may be considered for a second year of funding based on a competitive renewal.

Submission Guidelines

The current application cycle is closed. For additional information please contact Michelle Callahan at [email protected].

2023 Awardees

Francesca Ferraro, MD, PhD

Acute myeloid leukemia (AML) is a deadly cancer in adults with limited treatment options and low survival rates of approximately 25% at 5 years. Our recent research brought to light the crucial role that the oncogene MYC and its protein network play in the initiation and maintenance of AML, regardless of genetic subtype. Specifically, during leukemogenesis MYC transcriptionally regulates a core signature of oncogenic target genes and interacts with a specific set of oncogenic proteins to promote leukemia initiation and maintenance.

Based on these data, we hypothesize that MYC coordinates key transcriptional and translational programs to initiate and promote AML, and that targeting these pathways will selectively kill AML cells that over express MYC while sparing normal cells. To accomplish this, in Aim 1, we will use a genetic based approach to target the core MYC-driven AML transcriptional programs and in Aim 2, we will use a pharmacologic approach to inhibit the oncogenic interactions between MYC and its proteins partners in freshly harvested AML cells, from bone marrow aspirates of AML patients at diagnosis. The impact of these approaches will be evaluated on the survival of leukemic versus control mice in Aim 1 and on the in vitro survival of human AML-cells versus normal hematopoietic cells in Aim 2. If successful, these experiments will deepen our understanding of the functions of MYC in AML and other MYC driven cancers and identify novel, selective, therapeutic vulnerabilities to broaden the therapeutic repertoire for the treatment of acute myeloid leukemia

Orsola Di Martino, PhD

Acute myeloid leukemia (AML) is characterized by high rates of chemotherapy resistance and relapse. Therefore, identifying the molecular underpinnings of chemotherapy resistance is a key first step in developing more-effective AML chemotherapies. We previously showed that AML cells treated with the first-line chemotherapies Ara-C and Doxorubicin display an increase of the transcription factor XBP1s and that inhibition of XBP1s impedes disease progression in experimental models of AML. We have identified the tumor suppressor protein DDIT4 (DNA-Damage Induced Transcript 4) as XBP1s target and potential mediator of chemotherapy resistance in AML. DDIT4 is a stress-activated protein induced by many cellular insults, including chemotherapy. Our preliminary observations show that elevated expression of DDIT4 is associated with worse outcomes in AML. Moreover, we observed that DDIT4 expression increases in AML cells exposed to Ara-C/Doxo, while DDIT4 inhibition causes AML cells to differentiate and die. Finally, using a BioID proximity-labeling system, we demonstrated that AraC/Doxo causes DDIT4 to localize to mitochondria where it interacts with key metabolic enzymes. We hypothesized that DDIT4 activation supports AML development and promotes the activation of chemoresistance mechanisms. We will test these hypotheses with the following specific aims:

1. Determine the relationship between XBP1s and DDIT4 in AML.

2. Define the role of DDIT4 in malignant and healthy hematopoiesis.

3. Define the molecular role of DDIT4 in AML chemotherapy resistance.

If successful, these studies will identify the metabolic regulators that promote chemotherapy resistance in AML and then use that information to develop highly effective therapies.

2022 Awardees

S PersaudStephen Persaud, MD, PhD

Project Title: Maximizing antileukemia effect and minimizing toxicity of antibody-based HSCT conditioning

With a 29% 5-year survival rate in adults, acute myeloid leukemia (AML) is among the most aggressive blood cancers. Allogeneic hematopoietic stem cell transplantation holds the potential for cure of AML by effectively “rebooting” a patient’s blood forming system with stem cells from a healthy donor. To prepare for transplant, patients undergo conditioning regimens comprised of chemotherapy and/or irradiation. These regimens deplete the patient’s hematopoietic stem cells to make space for the transplanted donor stem cells and destroy leukemia cells that survived their previous therapies. However, chemotherapy and irradiation cause dangerous toxicities that may prevent elderly or infirmed patients from undergoing transplantation. Since AML is predominantly diagnosed in elderly patients, it is critical to develop transplant conditioning approaches that avoid toxicities while maintaining therapeutic benefit.

Our research program seeks to address this unmet need by investigating conditioning strategies that promote the benefits and limit the adverse effects of stem cell transplantation. We previously showed that conditioning with antibody-drug conjugates achieved the therapeutic goals of transplantation without requiring chemotherapy or irradiation. In Aim 1 of this proposal, we will identify toxic payloads for antibody-drug conjugates that optimally ablate mouse and human stem cells and leukemia cells with minimal off-target toxicity. In Aim 2, we will develop novel toxin-free, antibody-based conditioning methods based on targeting cKit and CD47, which we hypothesize will deplete stem and leukemia cells with the optimal safety profile. Collectively, these studies will advance antibody-based conditioning towards our goal of achieving maximal antileukemia benefit with minimal patient harm.

Jeff-BednarskiJeffrey Bednarski BS, MD, PhD

Project Title: Role of BCLAF1 in leukemic transformation

Acute myelogenous leukemia (AML) remains a difficult to treat subtype of leukemia. While current therapies induce remissions, nearly half of all patients will relapse. Further, AML therapies are associated with significant toxicities. New treatment approaches that selectively target AML cells are needed. To this end, it is critical to understand the programs that support the development and persistence of leukemia cells. AML leukemic blasts often hijack pathways from normal bone marrow cells to drive growth of the malignant cells. Normal bone marrow stem cells have a unique ability to continue to divide throughout life. This “self-renewal “capability is critical for sustaining production of blood cells. However, errant activation of these self-renewal programs in AML cells promotes growth and survival of the leukemia. The mechanisms underlying how these pathways are corrupted in AML are not known. Our recent work has identified a new gene, BCLAF1, that regulates stem cell development and also has a role in leukemia. Our goal is to understand how BCLAF1 regulates development and persistence of AML and how the activities of BCLAF1 are different in normal stem cells versus malignant leukemia cells. Our work is focused on determining the mechanisms by which BCLAF1 functions in AML. We expect these studies will provide important insights into the programs underlying AML development and will reveal opportunities for developing novel, selective therapies for AML.

Yoon KangYoon Kang, PhD

Project Title: Redirecting myeloid differentiation trajectory to treat Myeloproliferative Neoplasms

Myeloproliferative neoplasms (MPNs) are a group of diseases characterized by too many white blood cells, red blood cells, or platelets in the bone marrow. There are several well-known disease-causing mutations and researchers try to develop treatments targeting those mutations. However, in many cases, several mutations are accumulated to develop disease phenotypes. There are also patients with no targetable driver mutations, or that develop resistance to targeted therapies. Therefore, a better understanding of the mechanisms underlying myeloid cell expansion, a shared feature of various MPNs, could help develop new treatments to be used in combination with current targeted therapies or as alternatives for patients not eligible for current therapies. My study aims to find a treatment, which is applicable to a broad range of MPNs independent of individual mutations. My previous work found that there is a specific immature bone marrow population, which is expanded in various MPN mouse models regardless of their driver mutations. In this study, I propose to study NF-KB signaling and GATA-2, two commonly dysregulated pathways in human myeloid malignancies, to control the production of distinct subsets of the expanded immature bone marrow population. My study will provide insights into the common mechanism underlying MPN development, and clues to develop broadly applicable therapeutic interventions.

2021 Awardees

Dr. Ferris

Margaret Ferris, MD, PhD (Awarded in 2020 and 2021)

Project Title: Defining the Interactome of RXRA in Leukemia

Retinoid receptors (retinoic acid receptors (RARs) and retinoid X receptors (RXRs)) are members of the nuclear receptor superfamily, which function as DNA-binding heterodimers and act as transcriptional regulators. The fusion protein PML-RARA is associated with acute promyelocytic leukemia (APL). All-trans retinoic acid (ATRA) is a ligand for RARA and is the prototype for differentiation therapy in APL. Treatment with ATRA relieves the pathognomonic differentiation block in APL. While ATRA therapy has revolutionized the treatment of APL, it has had more modest efficacy in other subsets of acute myeloid leukemia (AML). Prior studies of the retinoid receptors in hematopoiesis and leukemogenesis have largely focused on RARA, with RXRA considered as a silent partner.

We have previously shown that hematopoietic cells are exposed in vivo to natural ligands that activate RXRA but not RARA and that retinoid combinations simultaneously targeting both elements of the RARA:RXRA heterodimer lead to profound synergy in MLL-AF9 leukemia (e.g. ATRA plus bexarotene). In addition, we identified a gain-of-function mutation in RXRA (DT448/9PP) that leads to leukemic maturation that is greater than co-stimulation of RXRA and RARA and which is independent of RARA activation. In year 1 of funding of a SPORE DRP grant, we found that activation of RXRA via ligand (bexarotene) or gain-of-function mutation (DT448/9PP) lead to overlapping upregulation of genes involved in myeloid differentiation. Protein interaction studies showed that both bexarotene treatment and DT448/9PP expression lead to recruitment of co-activators and myeloid transcription factors (Cebpb and Cebpe). DT448/9PP also recruits a kinase, Pak2, that has been shown to activate RARA via phosphorylation of c-Myc.

Kim Miriam

Miriam Kim, MD

Project Title: CD7 Deleted HSCs To Restore Immunity After CAR T Therapy for T Cell Malignancies

We propose to develop gene edited hematopoietic stem cells (HSCs) as a supplemental therapy for T cell malignancies. We have previously developed genetically engineered immune cells to attack T cell leukemia, termed “chimeric antigen receptor (CAR) T cells”. These immune cells have been engineered to express a receptor on the cell surface that enables them to recognize and kill leukemia cells that would otherwise be invisible to the immune system. However, the CAR T cells cannot discriminate between malignant cells and their normal counterparts, and so this treatment can lead to loss of normal immune cells that are critical to maintain immune defense against infectious agents. Therefore, we have now developed a strategy to modify HSCs so that they can generate normal immune cells that are no longer susceptible to attack by the CAR T cells. We plan to perform detailed analyses to ensure that the gene-edited HSCs and the ensuing hematopoietic system are functionally intact. Any deficiencies in these gene-edited cells may tip the risk-benefit ratio of using this as a therapy for patients, and so would be important to illuminate prior to moving forward with this strategy. We hope that these studies can provide a pathway to using powerful immune therapies for patients with T cell malignancies without causing intolerable toxicity.

Link DanielDaniel Link, MD 

Project Title: Targeting ATR in TP53-mutated AML/MDS

Acute myeloid  leukemia (AML) that carries mutations in the TP53 gene carry a dismal prognosis  with a median survival of less than 6 months.   Most patients respond poorly, if at all, to standard leukemia chemotherapy.  Thus, there is a pressing unmet clinical need for better therapies for these patients.  In this research, we will test a novel therapy for TP53-mutated AML and/or myelodysplastic syndrome.  Specifically, our data suggest that AML cells with mutated TP53 are susceptible to inhibition of the ATR protein with AZD6738, a drug under clinical development. We will test the ability of AZD6738 in combination with other leukemia drugs to kill AML cells. If successful, this research would provide the foundation for a clinical trial in this very high risk group of AML/MDS with limited treatment options.

2020 Awardees

Dr. Singh

Nathan Singh, MD, MS (Awarded in 2020 and 2021)

Project Title: Etiologies of chimeric antigen receptor T cell dysfunction in acute leukemia

Chimeric antigen receptor CAR T cells (CAR T) have revolutionized the treatment of patients with B cell cancers, particularly pediatric and young-adult patients with relapsed or refractory acute lymphoblastic leukemia (ALL) – a disease with historically very-poor outcomes. Nearly 85% of these patients treated with CAR therapy will go into complete remission after treatment. The unfortunate reality, however, is that only half of these patients will experience lasting responses. For the small fraction of patients who don’t respond (~15%) and the larger fraction of patients who relapse (~40%) after CAR therapy it appears that failure of transferred T cells is the primary barrier to successful leukemia eradication. We recently found that prolonged exposure to leukemia cells, which occurs in all patients who do not respond or relapse, directly causes CAR T failure which permits disease progression. This is the first identification of a mechanism responsible for the most-common barrier to CAR T success.

This proposal aims to build on this finding and understand how prolonged exposure to leukemia re-programs CAR T cells to fail. Using a combination of laboratory-based models and evaluation of samples from patients who have received CAR therapy, we will develop a blueprint of the cellular processes that lead to failure.

This will directly lead to the identification of failure-promoting pathways and reveal molecular targets that can be manipulated to prevent CAR T failure using advanced cellular engineering technologies. These failure-resistant

CAR T cells will lead to more effective and durable remissions for patients with ALL.

C Katerndahl

Casey Katerndahl, PhD

Project Title: The role of GATA2 in myeloid progenitor self-renewal and transformation

Approximately 20,000 new cases of acute myeloid leukemia (AML) occur annually in the US. AML chemotherapy damages all dividing cells in the body non-specifically, thus leading to many serious side effects; although bone marrow transplantation can be curative, it also has many side effects, which result in the death of 20% of patients from the complications of the procedure. Overall, AML patients have a 5-year survival of only ~25%. Clearly, there is a great need for more specific, more effective, and less toxic therapies. But to achieve these goals, we

need a much better understanding of the cellular and genetic mechanisms that cause AML; we hope that this information could be used to exploit these mechanisms therapeutically. We use several well-characterized models of AML, in combination with the most modern laboratory techniques, to better understand how specific genes affect the initiation and progression of AML. We recently identified a gene called GATA2 as potential regulator of AML, and we are now beginning to understand how important GATA2 is as leukemia suppressor, and how to restore its function in AML cells. When mutations in this gene are inherited, they greatly increase the lifetime risk of AML; when mutations are acquired in adult life, that can accelerate AML progression by unknown mechanisms, which we intend to define in this proposal. This knowledge may allow us to design novel strategies to restore the function of this gene in AML cells as a therapeutic strategy for AML patients.

Margaret Ferris, MD, PhD 

Project Title: Defining the Interactome of RXRA in Leukemia

Retinoid receptors play an important role in blood development. These receptors are interesting because they can be turned on or off using small molecule drugs called retinoids, and because retinoids successfully cure most patients with a rare form of leukemia called acute promyelocytic leukemia. Retinoid responses are also observed in other forms of acute leukemia, but responses have tended to be less robust or durable. The mechanisms of retinoid responses in leukemia remain poorly understood but could be leveraged to improve retinoids as active drugs or to select additional patients who could respond to retinoids. The goal of this project is to define the mechanisms of retinoid anti-leukemic effects using state-of-the-art, unbiased, genome-wide techniques. We will use three different approaches that will characterize the changes in protein interactions and DNA binding that occur when retinoid receptors are exposed to retinoid treatment. These experiments will define the molecular consequences of turning on retinoid receptors in leukemia cells. Our future goals will be to leverage this information to improve retinoids as anti-leukemic therapeutics and to expand their use to additional patients.

2019 Awardees


Melissa Berrien-Elliott, PhD

Project title: Chimeric antigen receptor modified memory-like (CAR-ML) NK cells for leukemia immunotherapy

Here we propose to test the pre-clinical efficacy of novel chimeric antigen receptor expressing, memory-like (CAR-ML) natural killer (NK) cells against acute leukemia. Acute myeloid leukemia (AML) is an aggressive cancer of developing myeloid cells that has poor prognosis, and poor long-term disease-free survival for patients treated with standard therapy. Acute lymphoblastic leukemia is the most common childhood cancer of developing lymphocytes. Recently, CAR-T cells have been approved for treating ALL, but are expensive and associated with severe toxicities, including cytokine-release syndrome.

We have established that human NK cells exhibit innate memory following a brief combined stimulation with interleukins (IL)-12, -15, and -18. Preliminary data demonstrates that memory-like NK cells exhibit significantly enhanced AML recognition, functionality, longevity, and proliferative potential compared to naive or control NK cells. Recent preliminary data also shows that administration of allogeneic memory-like NK cells is safe, feasible, and results in clinical responses in both adult and pediatric AML patients. We hypothesize that approaches that enhance tumor targeting (CAR) will improve the clinical efficacy of memory-like NK cells, while minimizing the toxicities associated with current CAR-based therapies. Here were will functionally characterize CD33 and CD19-scFv expressing CAR-ML NK cells against CD33+ and CD19+ AML/ALL targets in vitro and define their efficacy in vivo using NSG-xenograft mouse models. Ultimately, these studies will provide the pre-clinical rationale for novel CAR-ML NK cell for treating acute leukemia.


Matt Walter, MD, and Zhongsheng You, PhD

Project Title: Targeting Nonsense-Mediated RNA Decay in Spliceosome Mutant Myeloid Malignancies

The goal of this project is to develop new ways to treat patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) that have mutations in a set of genes involved in RNA splicing (spliceosome genes). Mutations in spliceosome genes in MDS and AML samples causes abnormal stitching together of RNA (i.e., RNA splicing) in a patient’s blood cells. We know from our prior studies that spliceosome mutant cancer cells are more sensitive to drugs that further perturb RNA splicing, raising the possibility that mutant cells are more reliant on a cells ability to degrade abnormal RNA. Nonsense-mediated RNA decay (NMD) is a pathway in our cells that removes abnormal RNA that harbor premature termination codons, which are generated in spliceosome mutant cells.

Our preliminary data suggest that spliceosome mutant cells are sensitive to a drug that inhibits NMD. The data support the hypothesis that spliceosome mutant cells are dependent on intact nonsense-mediated RNA decay for survival. We will test this possibility using several approaches. We will determine whether expressing a wide-range of spliceosome gene mutations makes blood cells sensitive to NMD inhibition using drugs and genetic approaches. Next, we will determine why spliceosome mutant cells are sensitive to NMD inhibition. Collectively, results from these experiments will be used to plan a clinical trial to treat MDS and AML patients with a new drug that can kill spliceosome mutant cancer cells and improve a patient’s outcome.

Oh Stephen

Stephen Oh, MD, PhD

Project title: Single Cell Spatial Characterization of Leukemic Transformation

The goal of this project is to identify and characterize specific cell types in the bone marrow of patients with myeloproliferative neoplasms (MPNs) that transform to acute leukemia. Utilizing a novel technology called imaging mass cytometry (IMC), we aim to determine where these cells reside in the bone marrow, and to thereby understand how they interact with neighboring cells to promote evolution to leukemia. By understanding how these cells behave in their resident locations, we seek to identify novel avenues for therapeutic intervention. In the long-term, we aim to devise strategies to broadly prevent the development of leukemia.

Dr. Oetjen

Karolyn Oetjen, MD, PhD

Project Title: Stromal interactions in myelodysplastic syndromes characterized by imaging mass cytometry

Myeloid neoplasms, including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), have complex interactions with the bone marrow environment. Normal blood development originates from hematopoietic stem cells, which are supported within a niche of bone marrow stromal cells. Many growth signals from cytokines in the hematopoietic stem cell niche may support malignant cell proliferation. Particularly in MDS, increased cytokines in the bone marrow environment are implicated in disease development.

Much of this understanding is from mouse models of disease, but characterizing MDS in patients has been more challenging due to limitations in technology and patient samples. Improvements in imaging now allow simultaneous visualization of up to 40 cell markers simultaneously. We propose to apply this innovative technology to biopsy specimens from patients with MDS in order to examine interactions of malignant cells with stromal cells in the bone marrow environment. Quantifying interactions in the hematopoietic niche will provide an understanding of the inflammatory milieu that drives MDS pathogenesis at an unprecedented scale.

2018 Awardees


Jaebok Choi, PhD, MA

Title: Enhancing Anti-Leukemia Effects of Hematopoietic Cell Transplantation

Bone marrow transplantation (BMT) remains the most effective treatment for patients with high risk and relapsed leukemia and other blood cancers. The therapeutic benefit of BMT for these hematologic malignancies is primarily derived from the donor’s tumor-fighting T cells also known as a graft-versus leukemia (GvL) effect. However, BMT also comes with the risk that the donor T cells in the transplant (graft) will become overzealous and begin to attack not only the leukemia, but also the patient’s skin, intestines, lung, and liver resulting in graft-versus-host disease (GvHD). These two effects of BMT are difficult to separate. As a result, immunosuppressive therapeutic strategies that are often used to prevent and treat GvHD may adversely affect a patient’s survival by reducing the beneficial GvL effect and consequently increasing malignancy relapse. Therefore, finding a means to enhance the GvL activity of T cells while eliminating their tendency to cause GvHD is a major clinical goal in the BMT field. However, the mechanisms by which allogeneic donor T cells differentially modulate GvHD and GvL remain largely unknown. This gap in our mechanistic understanding hinders our ability to treat GvHD while preserving GvL. Accordingly, we will, for the first time, identify novel GvL- vs GvHD associated molecular targets using an unbiased genome-wide CRISPR/Cas9 library. Our study will mechanistically dissect GvHD vs. GvL and provide insights into novel therapeutic strategies to enhance GvL while eliminating GvHD.


John Welch, PhD

Title: Optimizing retinoids for acute myeloid leukemia

Current therapy for acute myeloid leukemia (AML) is toxic and only cures about 30% of patients. We need better drugs with fewer side-effects. In this project, we will explore the potential of two drugs in AML, all-trans retinoic acid (ATRA) and bexarotene. These are both pills, they are FDA approved, and they have very tolerable side-effects. We found that the combination has striking synergy and leads to cell death in aggressive leukemia models in vitro, which contrasts with the modest outcomes we observe when they are used as single agents in AML patients. In this study, we seek to better understand the molecular mechanisms that facilitate synergy and to chemically optimize bexarotene to treat AML patients. ATRA and bexarotene bind to two respective proteins, RARA and RXRA, which form a single complex. We think synergy occurs because inhibitory proteins can only be displaced from this complex when both ATRA and bexarotene bind. Many derivatives of bexarotene have been synthesized by other groups. We will combine the best chemical features of these compounds to see if we can develop a single drug with better activity and fewer side effects. Mechanistic discoveries will be used to determine the optimal characteristics of retinoids for AML treatment and to refine our drug development. In parallel, we are working to develop a clinical trial of combination ATRA and bexarotene. We hope to learn from this initial trial and then develop future trials with more optimized and AML-specific compounds.

2017 Awardees

Matthew Cooper, PhD

Matthew Cooper, PhD

Title: “Off the shelf” fratricide resistant CAR-T for the treatment of T Cell malignancies

T cell malignancies represent a class of devastating hematologic cancers with high rates of relapse and mortality in both children and adults for which there are currently no effective or targeted therapies.  Despite intensive multi-agent chemotherapy regimens, fewer than 50% of adults and 75% of children with T-ALL survive beyond five years. For those who relapse after initial therapy, salvage chemotherapy regimens induce remissions in 20-40% of cases. Thus, a targeted therapy against T cell malignancies represents a significant unmet medical need.

 T cells engineered to express a chimeric antigen receptor (CAR) are a promising cancer immunotherapy. Such targeted therapies have shown great potential for inducing both remissions and even long-term, relapse-free survival in patients with B cell leukemia and lymphoma.  However, shared expression of target antigens between T effector cells and T cell malignancies has limited development of CAR-T targeting T cell neoplasms due to unintended self-killing of CAR-T (fratricide) and an inability to collect sufficient T cell for CAR-T generation from the patient. Using CRISPR/Cas9 gene editing techniques, we have overcome these obstacles to generate CAR-T effective at killing T cell cancers.  The goal of this project is to further develop gene edited CAR-T against T cell malignancies, the first clinically feasible adoptive T cell therapy for T cell leukemia and T cell non-Hodgkin’s lymphoma.

Qiang Zhang, PhD

Qiang Zhang, PhD

Project title:  Stabilizing AML Cells for Comprehensive Global Proteomic Analysis

In studying the causes of leukemia, researchers have discovered multiple genomic faults that are associated with disease progression and recurrence. DNA testing overlooks another potential contributor to disease, proteins that may be driving leukemic cells and also could be targeted with existing and new treatments. If DNA can be described as the body’s genetic blueprint, proteins may be thought of as the construction workers who carry out the plan.

Studying the blueprint can be vital to understanding genetic diseases, including leukemia, but that focus also means that some problems arising with the workers may be missed. Proteogenomics is emerging as a science to integrate these two streams of patient information. This work will assess the potential and develop the facility to use genomically well-characterized banked leukemia cells for next-generation proteomics. Success will make possible the study of large numbers of patients using proteogenomics to discover new biomarkers and drug targets for leukemia.

2016 Awardees

Dr. FehnigerTodd Fehniger, MD, PhD 

Project title:  Enhancing MHC-haploidentical HCT with donor memory-like NK cell adoptive immunotherapy

This project develops a new strategy to harness the immune system to fight leukemia, and pilots this idea an early phase clinical trial for patients with relapsed or refractory (rel/ref) acute myeloid leukemia (AML).  The study harnesses natural killer (NK) cells, which are immune cells that a naturally able to recognize and eliminate cancerous cells.  Recent work has shown that activating donor NK cells with three cytokines (IL-12, IL-15 and IL-18), hormone signals used by immune cells to communicate, resulted in a long-lived, highly potent NK cell type called memory-like NK cells.  This project combines memory-like NK cell therapy and a standard “mini” hematopoietic cell transplant from the same donor, and will test the ability of memory-like NK cells to expand, proliferate, persist, and fight leukemia in patients with leukemia.  This developmental project will lead a larger phase 2 study using this same strategy for patient with relapsed or refractory AML.

Grant Challen

Grant Challen, PhD

Project title: Identifying novel dependencies in pre-leukemic HSCs

Epigenetics is a term used to refer to modifications to the genome which change the properties of cells, without changing the sequence of the DNA itself.  Epigenetic modifications such as DNA methylation act like a blueprint to maintain cell identity by informing each specific cell type which genes should be switched on or off.  Abnormal distribution of epigenetic marks is associated with a variety of human cancers, most notably blood cancer such as acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).  Furthermore, genome sequencing studies have revealed that almost half of all patients with AML and MDS have genetic mutations in some component of the molecular machinery that is responsible for regulating these DNA methylation marks.  Two of the most commonly mutated genes in these diseases are DNMT3A and TET2, which respectively function to add and remove DNA methylation from the genome.  However, analysis of these patients has not revealed consistent DNA methylation differences that explain how the mutations cause cancer.  As these mutations often make the cancers resistant to conventional chemotherapy, there is an urgent need to better understand how these mutations contribute to cancer to develop more optimal therapies. 

Our hypothesis is that epigenetic changes other than DNA methylation are key contributors to the disease in patients with these mutations.  In this project, we will identify epigenetic pathways which are crucial to the survival of cells with DNMT3A and TET2 mutations with the goal of identifying new avenues for therapy in these patients.  Our primary tools to study this are mouse models we have in the lab which carry genetic mutations in the genes DNMT3A and TET2, which we have shown develop a disease resembling human MDS.  We will use the bone marrow stem cells from these mice to identify what other factors are important for cancer initiation by “knocking out” specific epigenetic regulators using a genome editing tool called CRISPR/Cas9.  This technology allows us to very rapidly and specifically remove other epigenetic modifying genes from the cells with pre-existing DNMT3A and TET2 mutations.  We then track all the mutant cells, and identify which genes are necessary for cancer by identifying which cells “disappear” from the mice over time using high-throughput genome sequencing.  Any mutations which disappear means that a particular gene was required for the survival of the cancer cells, as without that gene the cancer cells die and are lost.  Thus, any mutations which disappear represent new drug targets for patients with DNMT3A and TET2 mutations.

Lee Ratner, MD, PhD
Project title: Role of protein kinase C mutations in adult T-cell Leukemia

Human T-cell leukemia virus type 1 (HTLV-1) is the cause of a T cell malignancy, adult T-cell leukemia lymphoma (ATL). This is a highly refractory malignancy, lacking effective treatment approaches, with a long-term survival rate of less than four percent. The current project is based on exciting new data that mutations are common in genes that code for components of a pathway that allows the T cell receptor to induce T cell growth. Notably, we found that one of these components, protein kinase C beta appears to be activated in about one third of cases through mutation, and an additional third of cases through alteration of proteins that turn-on protein kinase c. We will determine if the most common protein kinase c mutation is important for the growth of T cells in mice, and the genes that are turned on by this mutant protein. We will also determine if the protein kinase c mutation is important for growth of human ATL cells in immunodeficient mice. In both murine models, we will determine what genes are activated by this mutant form of protein kinase c. In addition, we will determine if a protein kinase c inhibitor, enzastaurin blocks T cell proliferation. Overall, these studies have the potential to lead to an important clinical advance in ATL treatment, which could have applications in other leukemias or lymphomas.

Clinical Trials

The Siteman Cancer Center offers many types of clinical trials, also called clinical studies or research protocols. At any given time, Siteman has more than 350 therapeutic trials under way.

For more information about any of the clinical trials listed on this site, call 314-747-7222 or 800-600-3606 toll free or e-mail [email protected].

SPORE In Touch Patient E-Newsletter


As part of its commitment to patient care, The Washington University SPORE in Leukemia team at Siteman Cancer Center publishes its e-newsletter, SPORE In Touch, for leukemia patients and their families. The goal of this newsletter is to provide valuable information as an extension of our mission to offer world-class care, research and resources within the clinical and medical research communities.

SPORE In Touch is a digital publication that is distributed via email three times a year, and focuses on issues related to leukemia, myelodysplastic syndromes or stem cell transplantation. It features patient stories, physician interviews, clinical trial information, events and other milestones.

To learn more about the publication, please email [email protected] or call 314-273-2607.

To sign up to receive the newsletter, please click here.

You are of course free to remove yourself from the newsletter distribution list at any time. We will never sell your information to a third party or use your contact information for any communication outside of the newsletter.

Contact Us

Siteman Cancer Center SPORE in Leukemia

Nancy Reidelberger
SPORE Administrator
Phone: 314-362-9337
Fax: 314-362-9333
Email: [email protected]

Michelle Callahan
Administrative Coordinator
Email: [email protected]

Investigators and Staff

Michelle Callahan
Administrative Coordinator
Email: [email protected]

John DiPersio, MD, PhD
Leader, Project 4
Phone: 314-454-8306
Fax: 314-454-7551
Email: [email protected]

Timothy Graubert, MD
Co-Leader, Project 3
Phone: 617-643-0670
Email: [email protected]

Timothy Ley, MD
Co-Leader, Project 1
Phone: 314-362-8831
Fax: 314-362-9333
Email: [email protected]

Daniel Link, MD
Principal Investigator; Leader, Project 2; Director, Core C; Co-Chair, DRP
Phone: 314-362-8771
Fax: 314-362-9333
Email: [email protected]

Graham Colditz, MD, DrPH
Director, Core B
Phone: 314-454-7940
Fax: 314-747-3935
Email: [email protected]

Nancy Reidelberger
SPORE Administrator
Phone: 314-362-9337
Fax: 314-362-9333
Email: [email protected]

Laura Schuettpelz, MD
Co-Chair, DRP
Phone: 314-286-1813
Fax: 314-286-2893
Email: [email protected]

Geoff Uy, MD
Co-Chair, CEP; Co-Leader, Project 2
Phone: 314-747-8439
Fax: 314-454-7551
Email: [email protected]

Matthew Walter, MD
Co-Chair, CEP; Co-Leader, Project 3
Phone: 314-362-9409
Fax: 314-362-9333
Email: [email protected]

Mark Watson, MD
Co-Director, Core A
Phone: 314-454-7919
Fax: 314-454-5208
Email: [email protected]

John Welch, MD, PhD
Leader, Project 1
Phone: 314-362-2626
Fax: 314-362-9333
Email: [email protected]

Peter Westervelt, MD, PhD
Director, Core A; Co-Leader, Project 4
Phone: 314-454-8323
Fax: 314-454-7551
Email: [email protected]