Career Enhancement Program

Career Enhancement Program

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 diverse 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, and will promote diversity among our young investigators. 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 2024

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 Dnmt3a^R878H or Npm1^cA 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 Dnmt3a^R878H x Npm1^cA mice, leading to the accelerated development of AML. Importantly, overexpression of Gab2 induces more limited expansion of hematopoietic cells with the Npm1^cA mutation only, and is selected against in cells with Dnmt3a^R878H 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 Dnmt3a^R878H x Npm1^cA 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.