Developmental Research Program

Program Directors

Laura Schuettpelz, Md, PhD (WashU)

Daniel C. Link, MD; (WashU)

The overall goal of the Leukemia SPORE Developmental Research Program (DRP) is to identify and support developmental research projects in leukemia for future peer-reviewed funding and/or future independent SPORE projects. Projects supported under the DRP will expand the scope of translational research and increase the number of investigators committed to leukemia research. The DRP will work in tandem with the Career Enhancement Program (CEP) to assist in the development and mentoring of junior investigators. To accomplish these goals, the DRP aims to:

1) support developmental research projects in leukemia for future incorporation as full SPORE projects or application for other major peer-reviewed funding;
2) foster collaborations between basic and clinical researchers;
3) provide mentoring to junior faculty; and
4) promote the participation of investigators in leukemia research and facilitate recruitment of patients to clinical leukemia trials.

DRP Awardees 2025

Melissa Mavers

Allogeneic hematopoietic stem cell transplantation (HSCT) remains an important treatment modality for high risk leukemias. However, graft-versus-host disease (GVHD) contributes significantly to transplant-related morbidity and mortality, limiting the utility of HSCT as a curative treatment option. Several studies suggest that invariant natural killer T (iNKT) cells can suppress GVHD in mouse models without losing the important graft-versus-leukemia effect, particularly iNKT cells with certain properties (known as Th2-like). Therefore, iNKT cells have significant potential as a novel off-the-shelf cellular therapy for GVHD prevention, yet the best approach for developing this cell therapy product remains to be determined. 

Cord blood has been increasingly utilized as a cell source for developing cellular therapies. Our laboratory studies have demonstrated that human cord blood-derived iNKT cells have a Th2-like transcriptional signature. However, the capacity for human cord blood-derived iNKT cells to suppress GVHD is not known. This project will establish the feasibility of developing a cord blood-derived iNKT cell product and test its efficacy in GVHD prevention as compared to peripheral blood-derived iNKT cells in preclinical models. The results from this project will lead directly to initiating our planned clinical trial of adoptive transfer of iNKT cells for prevention of GVHD. Our overall goal is to establish a new paradigm in GVHD prevention to reduce GVHD rates and severity, leading to increased survival and improved quality of life for leukemia patients undergoing HSCT.  

Abby Green and Jeff Bednarski

Precursor B cell acute lymphoblastic leukemia (pre-B ALL) is the most common childhood cancer. The ETV6-RUNX1 translocation is present in 25% of childhood ALL, making it the most prevalent genomic aberration among childhood leukemias. While many patients with ETV6-RUNX1-translocated ALL have favorable outcomes, the incidence of late relapse is substantial (15-20%) therefore this project aims to gain a mechanistic understanding of disease drivers to develop improved therapeutic strategies. It is well established that the ETV6-RUNX1 translocation by itself cannot transform B cells to leukemia. Prior studies indicate that the endogenous mutagen APOBEC3A is highly active in pre-B ALL with ETV6-RUNX1 translocations. Our data indicate that ETV6-RUNX1 promotes an inflammatory transcriptional program, including upregulation of APOBEC3A. We are seeking to define how APOBEC3A becomes dysregulated in pre-B cells with ETV6-RUNX1 translocations and what impact that mutagenesis has on malignant transformation. Ultimately, this project will improve our understanding of endogenous mutagenesis driving childhood leukemia and will define therapeutic vulnerabilities and/or opportunities to prevent mutagenesis in vulnerable hosts.

DRP Awardees 2024

Grant Challen

Myeloproliferative neoplasms (MPNs) are diseases characterized by unregulated production of one or more blood cell types such as red blood cells or platelets. There are more than 300,000 MPN patients in the United States. Genetic mutations acquired in bone marrow cells that activate a signaling pathway called JAK/STAT are the most common causes of MPN. Due to this, drugs that inhibit this JAK/STAT signaling like ruxolitinib are the standard treatments for these patients. While these drugs offer significant improvements in some MPN symptoms, they ultimately do not improve overall survival. New drugs that target these mutant cells more specifically are needed for a cure. Our lab studies have identified a critical role for the gene JARID2 in MPN. When this gene is mutated in MPN patients, the cells grow much faster leading to disease progression  into secondary acute myeloid leukemia (sAML). We have used laboratory models to understand how this process happens. In doing so, we found that MPN cells do not grow well when JARID2 levels are increased. If we could increase JARID2 levels in MPN patients, it may eradicate their disease. As drugs to increase protein levels are rare, to test this idea we will inhibit another protein that targets JARID2 for degradation. By doing this, we can indirectly increase JARID2 levels in MPN cells. This project will test the impact of increasing JARID2 in MPN cells in both mouse models and patient cells with the goal to credential this as a new druggable target for MPN patients.

Yang Li

Myeloproliferative neoplasm (MPN) is a type of blood cancer where the body makes too many blood cells such as platelets, white blood cells, and red blood cells. It’s caused by gene mutations that make cells grow uncontrollably due to the activation of a pro-cancer pathway called JAK-STAT. Current treatments work by inhibiting the JAK-STAT pathway. It can help to manage symptoms but can’t cure the disease. Sometimes, MPN can turn into a faster-growing and more severe type of leukemia called secondary acute myeloid leukemia (sAML).

Unfortunately, JAK-STAT inhibition and standard treatments for regular leukemia don’t work well for sAML. Epigenetics is a bridge between genes and RNA (which provides instruction to make proteins, the functional unit of our body). All cells in the human body have the same set of genes but we have different types of cells (muscles,bones, liver … etc). This difference is largely attributed to the intricate regulation of epigenetics so that some genes are expressed and some are not. In other words, epigenetics looks at how genes are controlled without changing the

DNA itself. Researchers have found that changes in these controls are enough to drive cancer development without gene mutation and are more common in sAML than regular leukemia. Thus ,our goal is to apply the most cutting edge technology to study serial patient samples before and after they develop sAML to understand how epigenetic alteration contributes to the progression from MPN to sAMl and the unique features of sAML in order to identify efficacious therapies.