Research

SPORE in Leukemia

Overview

Principal Investigator: Daniel Link, MD

The Specialized Programs of Research Excellence (SPORE) are the cornerstone of the National Cancer Institute’s effort to promote collaborative, interdisciplinary translational cancer research. Each SPORE is focused on a specific organ site and is designed to enable the rapid and efficient movement of basic scientific findings into clinical settings as well as to determine the biological basis for observations made in individuals with cancer.

The Washington University SPORE in Leukemia is one of only three SPOREs in the United States focused on leukemias and myelodysplastic syndromes (MDS). Washington University has been at the forefront of genomic studies in AML and MDS. This ongoing basic research has identified several novel recurring mutations in MDS/AML and is defining the importance of clonal heterogeneity in AML or MDS to clinical outcome. In this SPORE, we leverage our expertise in cancer genomics, immunology, and hematopoiesis to develop innovative translational research in leukemia. Our long-term goal is to develop novel biomarkers and treatments for leukemias and MDS and to develop and promote innovative translational leukemia research.

Our SPORE in Leukemia includes the following four translational projects:

Project 1:  Molecular determinants of decitabine responsiveness
  • Basic Science Co-Leader: Timothy Ley, MD
  • Clinical Science Co-Leader: John Welch, MD, PhD
Project 2:  Targeting the bone marrow microenvironment in acute lymphocytic
leukemia
  • Basic Science Co-Leader: Daniel Link, MD
  • Clinical Science Co-Leader: Geoffrey Uy, MD
Project 3:  Development of RNA splicing modulators for myelodysplastic syndromes and AML
  • Basic Science Co-Leader: Timothy Graubert, MD
  • Clinical Science Co-Leader: Matthew Walter, MD
Project 4: Epigenetic modulation of graft versus host disease and graft versus leukemia
  • Basic Science Co-Leader: John F. DiPersio, MD, PhD
  • Clinical Science Co-Leader: Peter Westevelt, MD, PhD

These projects are supported by three shared resources:

  1. Biospecimen Processing
  2. Biostatistics
  3. Administration

This SPORE also supports a Career Development 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

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, and Geoffrey Uy, 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.

Eligibility

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.

Awards

One to two awards of $60,000 (direct cost) will be made annually. The second year of funding is contingent upon adequate progress.

Submission Guidelines

The current application cycle is now open. Applications will be accepted until May 1, 2017 with funding to begin July 1, 2017. Applications must be submitted through proposalCENTRAL. For additional information, please contact Amy Abrams at a.abrams@wustl.edu.

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.

2015 Awardees


Cooper_MattMatthew Cooper, PhD

Project title: Combination therapy of immunomodulating agents for AML treatment in a novel human CD3ε mouse

Recent advances in immunotherapy have demonstrated the potential of harnessing the immune system to fight cancer.  Progress in this area has been hampered by a lack of an animal model to test new immunotherapy reagents, such as bispecific antibodies that direct immune cells to attach cancer cells.  To this end, we have generated a novel transgenic mouse model that may overcome this limitation.  Specifically, we are performing studies to see if this mouse model will allow us to test new bispecific antibodies for their ability to activate the immune system against leukemia. 

Duncavage_EricEric Duncavage, MD
Project Title:  Quantitative tumor burden monitoring in myelodysplastic syndromes

Myelodysplastic syndromes (MDS) are a heterogeneous group of diseases characterized by persistent low blood counts, cellular dysplasia, and an increased risk of transformation to leukemia with an average annual incidence of 45,000 cases.  While many patients with MDS are treated with prolonged courses of non-cytotoxic chemotherapy, up to one third of cases will eventually progress to acute leukemia and require treatment with cytotoxic chemotherapy or allogenic bone marrow transplant.  A major unmet clinical need is the ability to accurately monitor MDS patients for treatment response and progression to leukemia. In this study we propose to use newly developed ultra-sensitive sequencing methods and multi-parameter flow cytometry to monitor disease burden in MDS patients in enrolled in clinical trials.  The data generated in this study will allow us to establish the feasibility of using rapid, inexpensive sequencing methods for monitoring of therapeutic response in MDS patients including using less-invasive peripheral blood samples.

Developmental Research Program (DRP)

Lee Ratner, MD, PhD, 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.

Eligibility

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.

Awards

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 now open.  Applications will be accepted until May 1, 2017 with funding to begin July 1, 2017.  Applications must be submitted through proposalCENTRAL.  For additional information, please contact Amy Abrams at a.abrams@wustl.edu.

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.

2015 Awardees

choi_kKyunghee Choi, PhD
Project title: TS-GATA-Ebox Gene Regulatory Network in HSC Derivation and Expansion

Embryonic stem (ES) or induced pluripotent stem (iPS) cells can, in theory, be used to generate unlimited amounts of virtually any tissue type.  There is tremendous interest in using these stem cells to regenerate heart, brain, blood, or other tissue in patients with cancer or degenerative diseases.  Our research will test a novel approach to enhance the differentiation of stem cells into blood cells.  Specifically, our data suggest that expression of three genes (ETV2, GATA2 and Scl) in ES cells should enhance the generation of functional hematopoietic (blood) stem cells.  This research, if successful, would provide a new source of blood stem cells to treat a wide variety of blood disorders, including leukemia. 

Lian_MMin Lian, MD, PhD, MPH
Project title: Multilevel determinants of survival among patients following HSCT

Leukemia, lymphoma and myeloma, are common hematopoietic malignancies in the United States. Hematopoietic stem cell transplant (HSCT) is a standard therapy procedure for patients diagnosed with primary hematopoietic malignancies. Despite well-known effectiveness of HSCT treatment, the survival of patients following HSCT still remains poor. We propose to conduct a multilevel analysis, using clinical data from patients who received HSCT due to these three hematopoietic malignancies, to identify risk factors (at multiple levels) associated with the survival of HSCT patients. We expect the study findings will help develop intervention strategy to improve the survival of patients following HSCT.

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 siteman@wudosis.wustl.edu.

SPORE In Touch Patient E-Newsletter

intouchspore

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 InTouch@dom.wustl.edu or call 314-747-2274.

To subscribe, please click here.

You are of course free to unsubscribe 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: nreidelb@wustl.edu

Amy Abrams
Administrative Coordinator
Phone: 314-747-2274
Fax: 314-362-9333
Email: a.abrams@wustl.edu

Investigators and Staff

Amy Abrams
Administrative Coordinator
Phone: 314-747-2274
Fax: 314-362-9333
Email: a.abrams@wustl.edu

Cara Baczewski
Research Administrator
Phone: 314-747-3705
Fax: 314-362-9333
Email: baczewski@wustl.edu

John DiPersio, MD, PhD
Leader, Project 4
Phone: 314-454-8306
Fax: 314-454-7551
Email: jdipersi@wustl.edu

Timothy Graubert, MD
Co-Leader, Project 3
Phone: 617-643-0670
Email: tgraubert@partners.org

Timothy Ley, MD
Co-Leader, Project 1
Phone: 314-362-8831
Fax: 314-362-9333
Email: timley@wustl.edu

Daniel Link, MD
Principal Investigator; Leader, Project 2; Director, Core C; Co-Chair, DRP
Phone: 314-362-8771
Fax: 314-362-9333
Email: danielclink@wustl.edu

J. Philip Miller, PhD
Director, Core B
Phone: 314-362-3617
Fax: 314-362-3728
Email: jphilipmiller@wustl.edu

Lee Ratner, MD, PhD
Chair, DRP
Phone: 314-362-8836
Fax: 314-747-2120
Email: lratner@wustl.edu

Nancy Reidelberger
SPORE Administrator
Phone: 314-362-9337
Fax: 314-362-9333
Email: nreidelb@wustl.edu

Geoff Uy, MD
Co-Chair, CEP; Co-Leader, Project 2
Phone: 314-747-8439
Fax: 314-454-7551
Email: guy@wustl.edu

Matthew Walter, MD
Co-Chair, CEP; Co-Leader, Project 3
Phone: 314-362-9409
Fax: 314-362-9333
Email: mjwalter@wustl.edu

Mark Watson, MD
Co-Director, Core A
Phone: 314-454-7919
Fax: 314-454-5208
Email: watsonm@wustl.edu

John Welch, MD, PhD
Leader, Project 1
Phone: 314-362-2626
Fax: 314-362-9333
Email: jwelch@wustl.edu

Peter Westervelt, MD, PhD
Director, Core A; Co-Leader, Project 4
Phone: 314-454-8323
Fax: 314-454-7551
Email: pwestervelt@wustl.edu