McArdle ProfessorJing Zhang Receives Competitive Renewal

McArdle Professor Jing Zhang recently received a 5-year competitive renewal of her grant “Molecular and Cellular Mechanisms of Chronic Myelomonocytic Leukemia (CMML)” from the National Cancer Institute. The grant, in its 11th year, will support Dr. Zhang’s continued research to understand the fundamental mechanisms of CMML.

CMML is a devastating cancer with an urgent and unmet need for effective therapies (median survival: ~28 months). Approximately 30% of CMML cases evolve to acute myeloid leukemia (AML) soon after their initial diagnosis, contributing to the poor prognosis of CMML patients.

Dr. Zhang said the lack of treatment options and poor outcomes for patients with hematopoietic stem cell malignancies led to the establishment of an international panel of laboratory and clinical experts. “During the past 5 years we have collaborated with this International Myelodysplastic/Myeloproliferative Consortium and demonstrated that concurrent NRAS and ASXL1 mutations define a population of CMML patients with shorter leukemia-free survival than those with ASXL1 mutations only.” On the basis of human data, members of Dr. Zhang’s laboratory then characterized NrasG12D/+; Asxl1-/- (NA) mice that model CMML patients with concurrent NRAS and ASXL1 mutations. NA mice developed CMML with accelerated progression and in ~50% of these mice CMML transformed to AML (secondary AML, sAML). Further studies with the NA mouse model showed that combined inhibition of certain proteins (MEK and pan-BET) led to downregulation of AP-1 transcription factor expression, partial mitigation of the suppressive immune microenvironment, enhancement of CD8 T cell cytotoxicity, and prolonged survival in NA-sAML mice.

“Based on our earlier studies, we hypothesize that Asxl1-/- and oncogenic Nras cooperate to accelerate CMML and promote its transformation to AML via reprogramming the immune microenvironment, which includes but may not limit to T cells”, says Dr. Zhang. Now Dr. Zhang and members of her laboratory are identifying the molecular and cellular mechanisms underlying the dysregulation of the immune microenvironment and determining whether immunomodulatory agents further improve the therapeutic effects of combined MEK and BET inhibition in NA mice through establishing durable anti-leukemia activities in immune cells.

Dr. Zhang, who was named the Centennial Professor of Oncology at UW-Madison in 2018, says the goal of this research is to “provide fundamental insights on the mechanisms of CMML that potentially could lead to effective, novel therapies for treating CMML and transformed AML.”