SPORE in Leukemia
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.
Principal Investigator: Daniel Link, MD
Our SPORE includes four translational research projects:
Project 1 Co-Leaders
John F. DiPersio, MD, PhD (WUSM) (Basic Science Leader)
Mike Rettig, PhD (WUSM) (Basic Science Co-Leader)
Armin Ghobadi, MD (WUSM) (Clinical Co-Leader)
Project 2 Co-Leaders:
Todd Fehniger, MD, PhD (WashU)
Project 3 Co-Leaders:
Matthew Walter, MD (Wash U) (Basic Science Co-Leader)
Timothy Graubert, MD (MGH) (Clinical Co-Leader)
Project 4 Co-leaders:
Geoffrey Uy, MD, PhD; (WashU) (Clinical Co-Leader)
Daniel C. Link, MD; (WashU) (Basic Science Co-Leader)
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.
Directors:
Meagan A. Jacoby, MD, PhD (WashU)
Mark A. Watson, MD, PhD (WashU)
The Biospecimen Processing Core (Core A) provides high-quality, clinically annotated biospecimens to all SPORE research projects and serves as a critical biospecimen resource to the broader leukemia research community. This core is responsible for identifying and enrolling every consenting patient referred to the Siteman Cancer Center with a newly diagnosed hematologic malignancy (excluding multiple myeloma). Biospecimens from these patients are collected at multiple timepoints, processed, cryopreserved, and stored for future studies. Detailed clinical data associated with each patient and biospecimen collection timepoint are collected prospectively to facilitate future sample selection and correlative analyses. This Core expands upon an existing CAP-accredited SCC biobank with additional, focused expertise, effort, and enabling technologies to comprehensively collect, annotate, process, quality review, and distribute biospecimens specifically for translational leukemia and leukemia-related cancer research. A further description of biospecimen resources available to the broader research community can be found on the NCI Specimen Resource Locator.
Directors:
Graham A. Colditz, MD, DRPh (WashU Medicine)
Malachi Griffith, PhD (WashU Medicine)
The Bioinformatics and Biostatistics Core (Core B) will support four leukemia research projects within this SPORE. The primary aim of Core B is to provide robust bioinformatics and statistical support to ensure rigorous and reproducible multi-omics analyses across preclinical studies, clinical trials, and clinical correlative studies. Core B’s services include guiding experimental design, data processing, and comprehensive analysis for a range of data types, including bulk RNA-seq, single-cell RNA-seq, CITE-seq, TCR-seq, whole genome sequencing (WGS), whole genome bisulfite sequencing (WGBS), ATAC-seq, scATAC-seq, CRISPR/Cas9 screens, and CyTOF experiments. By leveraging advanced bioinformatics tools and statistical methodologies, Core B enhances the precision and depth of data interpretation. In supporting the projects, Core B will enhance understanding of new treatment avenues pursued by each project including chimeric antigen receptor T-cell (CART) therapy for T-cell cancers, natural killer (NK) cell therapy for acute myeloid leukemia (AML), and targeted therapies for specific gene mutations in myeloid cancers. Through rigorous design and analysis of clinical trials and preclinical studies, Core B ensures that each project achieves its scientific objectives. Core B fosters a collaborative environment, offering consultation and training to researchers, thereby promoting the effective application of bioinformatics and biostatistics in leukemia research.
Director:
The Administration Core will provide 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, comply with all local and federal guidelines for grant administration, and facilitate communication and collaboration among the program members and with other Leukemia SPOREs. Accordingly, the specific aims of the Administration Core are as follows:
Aim 1. To facilitate intra- and inter-SPORE communication and collaboration.
Aim 2. To provide administrative and fiscal oversight and support for all SPORE components.
Aim 3. To coordinate activities of the SPORE Developmental Research Program.
Aim 4. To coordinate activities of the SPORE Career Enhancement Program.
Aim 5. To assist investigators with the preparation of scholarly presentations, publications, regulatory documents, and all other SPORE-related paperwork.
Aim 6. To encourage participation in SPORE activities.
Aim 7. To ensure that advocacy issues are addressed and included in all aspects of research involving patients.
Program Directors
Matt Walter, MD (Wash U)
Geoffrey Uy, MD (Wash U)
Timothy J. Ley, MD (Wash U)
The Leukemia SPORE Career Enhancement Program (CEP) has a goal of recruiting and supporting a set of new investigators in the field of translational leukemia research. To accomplish this objective, the CEP will provide financial support and mentored research training. It will leverage institutional strengths to recruit basic scientists and clinical investigators from varied disciplines and backgrounds to promote multidisciplinary translational research.
These goals will be accomplished in three ways:
1) We will recruit and financially support new investigators in the field of translational leukemia research.
2) We will provide training and mentoring to junior faculty from all backgrounds in translational leukemia research. CEP will work with new investigators to craft an individualized career development plan that may combine didactic coursework, patient care, and career skills tailored to their individual goals.
3) We will foster inter-SPORE collaborations.
We have established educational exchanges to provide CEP awardees the opportunity to present their research and meet with the leadership at a peer Leukemia SPORE Institution.
CEP Awardee 2025
Stefan P. Tarnawsky
The Role of TP53 in Mutant U2AF1 Myelodysplastic Syndromes
The goal of this project is to identify how splicing factor gene mutations regulate the growth of hematopoietic stem and progenitor cells (HSPCs) and to develop novel therapies to treat patients with myeloid neoplasms such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).
Among genes frequently mutated in clonal hematopoiesis, splicing factor gene mutations (e.g. U2AF1, SRSF2) have the highest growth advantage and the highest risk of progression to malignancy. However, in both human and mouse models, splicing factor gene mutations consistently reduce HSPC growth, compared to controls. Our preliminary in vitro and in vivo data suggest that the impaired growth of HSPCs expressing the common U2AF1S34F mutation is due to activation of TP53. This paradoxical finding suggests that for splicing factor mutant HSPCs to cause myeloid neoplasms, they must first overcome growth-suppressing signals. Understanding how splicing factor gene mutations initially impair the growth of HSPCs is the first step in understanding how mutant cells later adapt, expand, and cause disease.
R-loops are naturally occurring DNA:RNA triple helices, whose formation must be tightly balanced with RNASEH1-mediated degradation to prevent stalled replication forks, DNA damage, and TP53 activation. R-loops accumulate in models of splicing factor mutant MDS. This suggests that the high TP53 activity and impaired growth of U2AF1S34F HSPCs may be due to their unresolved R-loops. We hypothesize that RnaseH1 overexpression will rescue the growth of U2af1S34F HSPCs in vivo by normalizing their R-loops and reducing TRP53 pathway activity. In parallel, the increased R-loops in MDS patients with splicing factor mutations indicates a tipped balance favoring R-loop formation > degradation. This suggests that further disruption of R-loop maintenance may preferentially kill splicing factor mutant cells by causing insurmountable replication stress. Using complementary genetic and pharmacologic approaches, we will test whether mouse and human MDS patient-derived U2AF1S34F HSPCs are preferentially sensitive to RNASEH1 inhibition due to an overwhelming accumulation of R-loops.
Collectively, this project will elucidate the mechanisms whereby splicing factor mutant HSPCs activate TP53, providing insight into how mutant cells adapt and expand in splicing factor mutant myeloid neoplasms. Our findings will nominate disrupting R-loop maintenance via RNASEH1 inhibition as a novel therapeutic strategy to treat the 50% of MDS patients and 20% of AML patients who have splicing factor gene mutations.
CEP Awardee 2024
Michael Kramer
The goal of this project is to identify druggable targets for Acute Myeloid Leukemia (AML) initiated by mutations in DNMT3A and NPM1, and to test and validate interventions that target these vulnerabilities.
NPM1 and DNMT3A are among the most commonly mutated genes in AML patients. These mutations co-occur more frequently than expected by chance, with ~15% of AML patients containing mutations in both genes. Based on this clinical observation, we have generated mouse models that recapitulate this synergy. Mice with either Dnmt3aR878H or Npm1cA mutations develop AML with a long latency (>12 months) and low penetrance, but mice with both mutations develop AML in 6-15 months with nearly 100% penetrance. We have characterized 11 independent, spontaneous AMLs from this model that rapidly cause fatal leukemias in secondary recipients. Whole genome sequencing revealed one or more human AML-like cooperating mutations in each tumor (e.g. mutations in Flt3, Idh2, Ptpn11, Kit, Nf1 and Cbl). Surprisingly, 11 of the 12 AMLs also had an amplification of murine chromosome 7 as the sole structural variant. Using publicly available data from similar mouse models, we identified a minimally amplified 8.9 Mbp region on chromosome 7 containing 209 genes. We identified Gab2 on this interval as a key candidate gene, since its expression is also increased in human AMLs, and since it is known to facilitate signaling from receptor tyrosine kinases (including FLT3) to downstream pathways. We have now shown that overexpression of Gab2 induces significant expansion of hematopoietic cells from Dnmt3aR878H x Npm1cA mice, leading to the accelerated development of AML. Importantly, overexpression of Gab2 induces more limited expansion of hematopoietic cells with the Npm1cA mutation only, and is selected against in cells with Dnmt3aR878H only, and in wildtype cells, suggesting that its actions may require the presence of both Dnmt3a and Npm1 mutations. We have also observed that knockout of Gab2 in fully transformed murine AML leads to slower growth of the AML cells. In this project we will aim to use these findings can be used to identify novel, druggable targets in human AMLs with mutations in DNMT3A and NPM1. Firstly, we will use CRISPR-Cas9 gene editing of GAB2 in primary human AML cells to evaluate whether GAB2 may be a potential therapeutic target in human AML. Secondly, we will perform a CRISPR-based “essentiality screen” of druggable targets in murine AML arising in Dnmt3aR878H x Npm1cA mice to identify additional potential therapeutic targets. Finally, we will evaluate the top candidate genes using CRISPR-mediated gene editing in primary human AML samples. If successful, these studies will identify additional therapeutic targets for AML cells initiated by DNMT3A and NPM1 mutations, with a long-term goal of translation in early-phase clinical trials.
Program Directors
Laura Schuettpelz, Md, PhD (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.