Pilot Project Abstract - Deininger, Michael, MD, PhD

Deininger, Michael, MD, PhD, Associate Professor, Dept. of Hematology and Medical Oncology, OHSU

“Pathogenesis of chronic myelomonocytic leukemia (CMML)”

We will apply HD SNP array technology to discover new genetic lesion in chronic myelomonocytic leukemia.

Chronic myelomonocytic leukemia (CMML) combines features of a myelodysplastic syndrome with those of a myeloproliferative disease (MPD). It affects mainly elderly individuals and has a poor prognosis (median survival from diagnosis approximately 20 months). Therapy consists of cytotoxic agents for reduction of elevated white blood cell counts as well as supportive care. The only curative treatment is allogeneic stem cell transplant, but most patients are not eligible due to age and concomitant medical conditions. While hypersensitivity to GM-CSF is a common feature of CMML cells, the pathogenesis is heterogeneous at the molecular level. RAS mutations occur in 30-40% of patients, and some 5-10% of patients have activating mutations in tyrosine kinases such as PDGFR and JAK2, while pathogenesis remains unclear in the remainder. Uniparental disomy (UPD), i.e. copy number neutral loss of heterozygosity (LOH) is emerging as a recurrent theme in the pathogenesis of MPD. The best example is the association of JAK2V617F with UPD of chromosome 9p in patients with polycythemia vera. To identify UPD, but also regions of genetic gain or loss and copy number changes in patients with CMML we will carry out genome-wide high density SNP array analysis using the Affymetrix 6.0 chip, comparing leukemia cell DNA with constitutional DNA (mouthwash). Downstream analysis will focus on regions with recurrent abnormalities and candidate genes involved in the GM-CSF hypersensitivity. Preliminary data generated with the pilot funding will be used to support an R01 application, which will propose studies to discover and validate new therapeutic targets in CMML