Akil Merchant

PIBBS MENTOR

Assistant Professor of Medicine
Hematology-Medicine

Research Topics

Cancer, Leukemia/Lymphoma, Stem Cells

Research Overview

The broad interest of the lab is in hematologic malignancies with a focus on the biology of normal and malignant hematopoietic stem cells.

Specifically, we study how Hedgehog signaling controls hematopoietic stem cell function and normal myeloid development and apply these insights to understanding the role of Hedgehog activation in acute and chronic leukemias. The Hedgehog pathway is a promising new target for cancer therapy, including leukemia, however the role of Hedgehog signaling in normal or malignant hematopoiesis is not well understood. The Hedgehog pathway consists of secreted Hedgehog ligands, the receptor Patched (Ptch), the positive effector Smoothened (Smo) at the cell membrane, and several intracellular mediators culminating in the Gli transcription factors. Previous studies in normal hematopoiesis and leukemia have focused primarily on the upstream modulators of the pathway Ptch and Smo, and have led to contradictory conclusions. Hedgehog pathway output is ultimately determined by the combinatorial effects of the downstream Gli transcription factors, or the “Gli code.” Our understanding of the Gli code is complicated by functional redundancy between Gli1 and Gli2 and tissue/context dependent activator or repressor functions for Gli2 and Gli3. We recently reported that Gli1 loss leads to defects in hematopoietic stem cell (HSC) and myeloid progenitor proliferation and defective stress hematopoiesis. The focus of my research is to decipher the Gli code in hematopoiesis and thus to understand the role of each Gli transcription factor in leukemia. We believe that insights gained from studying the Gli factors in normal hematopoiesis will lead to a better understanding of their role in leukemia. Others have reported that loss of Smo leads to a delay in disease progression and depletion of leukemia stem cells in a BCR-abl induced murine leukemia model. We have observed that constitutively active Smo (SmoM2) can drive progression of chronic myeloproliferative disease (MPD) to acute leukemia in a FLT3-ITD model and that this is associated with expansion of the cancer stem cell (CSC) compartment. We hope to determine which Gli activators are required for disease progression from MPD to acute leukemia in the FLT3-ITD model and if loss of Gli3 suppression is sufficient to augment disease progression. A more sophisticated understanding of the role of individual Gli factors in cancer will aid in optimally selecting patients for treatment with Hedgehog inhibitors, help predict the hematopoietic toxicities of Hedgehog inhibitors, and will guide the design of drugs that can directly target the Gli factors.

A second focus of the lab is on the NRF2-KEAP1 pathway and its role in normal hematopoietic stem cells and leukemic stem cells. Nuclear factor erythroid-2–related factor 2 (NRF2) is a redox-sensitive transcription factor that plays a central role in the cellular response to oxidative stress. We recently reported that Nrf2 regulates the survival of murine HSC. We have observed that the expression of NRF2 correlates with in vitro chemosensitivity in acute myeloid leukemia (AML) cell lines and that targeting NRF2 induces chemosensitivity in leukemia cells. We have also found that NRF2 is highly expressed in leukemia stem cells, which are highly chemoresistant and are thought to be the cause of late relapse. We, therefore, hypothesize that NRF2 is a master regulator of chemoresistance in leukemia and that increased NRF2 activity will predict poorer response to treatment and worse overall prognosis. We are currently developing methods to use NRF2 activity as a prognostic and predictive biomarker in hematologic malignancies and hope to develop inhibitors of that pathway that can be used to induce chemosensitivity in tumors.