Aberrant Activity of RUNX1 in Juvenile Myelomonocytic Leukemia
Mentor: Alan Cantor
Juvenile Myelomonocytic Leukemia (JMML) is an aggressive myeloproliferative neoplasm of young children. The only current curative treatment is stem cell transplantation. Yet about 50% of children still die from recurrent disease. JMML is caused by activating mutations in Shp2 (PTPN11) and RAS pathway proteins. However, their key downstream transcriptional effectors remain unknown. My laboratory discovered that the hematopoietic transcription factor RUNX1 is directly activated by Shp2, a tyrosine phosphatase. RUNX1 is also activated by ERK-mediated serine phosphorylation downstream of active RAS signaling. Based on these findings, we hypothesize that RUNX1 over activation plays a key role in JMML pathophysiology. In preliminary data, we showed that (a) over expression of a mutant RUNX1 molecule that mimics constitutive activation by Shp2 leads to cytokine-independent cell growth and a myeloproliferative phenotype; (b) genetic RUNX1 haploinsufficiency markedly reduces disease severity in a JMML mouse model; (c) RUNX1 small molecule inhibitors reduce cytokine independent growth from these animals in vitro; and (d) differentially expressed genes in JMML patients are enriched for RUNX1 targets. Collectively, these data support RUNX1 as a novel therapeutic target in JMML. The aims are to: (1) determine the extent to which Shp2 mutations found in JMML patients directly activate RUNX1 transcriptional activity using transcriptional reporter assays; and (2) determine the extent to which pharmacologic RUNX1 inhibition reduces GM-CSF hypersensitivity of JMML primary patient samples. Positive results will provide key preclinical data to begin translating this new pharmacologic approach into a new treatment for children with JMML.
