Identifying therapeutic vulnerabilities in high-risk EVI1-positive myelodysplastic syndromes
EvansMDS Young Investigator Award
Myelodysplastic syndromes (MDS) represent a heterogeneous but commonly occurring group of hematologic malignancies characterized by aberrant blood cell formation causing cytopenias in various degrees. Allogeneic hematopoietic stem cell transplantation is the only curative therapy, but disease progression and transformation to acute myeloid leukemia (AML) remain a persistent problem for MDS patients. Prognostic risk factors that are associated with outcomes include, among other factors, cytogenetic abnormalities. Previous studies have revealed that MDS characterized by overexpression of the oncogenic transcription factor ecotropic viral integration site 1 (EVI1) have a particularly poor prognosis with inferior overall survival and a high rate of transformation to AML. Median survival for these MDS patients was similar to that for patients with therapy-related MDS. This subgroup of poor-risk Evi1 high MDS represents an area of unmet need requiring more effective novel therapeutic strategies to improve clinical outcomes for MDS patients.
Building upon my prior work in credentialing novel therapies for hematologic malignancies, we have now discovered that leukemia patients with a specific genetic subtype (e.g. inversion of chromosome 3), characterized by high expression of the oncogenic transcription factor EVI1 and poor remission rates with standard induction chemotherapy, exhibit robust responses to treatment with the recently FDA-approved combination of azacitidine and venetoclax. Based on this striking observation, we hope to test whether this therapeutic combination is equally effective in EVI1-positive MDS by employing a mouse model of MDS driven by overexpression of Evi1 as well as patient-derived xenografts of EVI1-positive MDS samples. Furthermore, we hope to apply a CRISPR-Cas9 screen in order to identify molecular determinants on chromosome 7 that mediate resistance to azacitidine/venetoclax. I believe that this approach will not only reveal undiscovered mechanisms of resistance but may provide the rationale for more effective combination therapies for an especially adverse-risk subtype of MDS.