The Trustees of Columbia University in the City of New York, Columbia University Medical Center
Project Term: July 1, 2019 - June 30, 2024
Bone marrow scar formation (fibrosis) is a hallmark of myelofibrosis and contributes significantly to the disease progression. We use mouse genetics to model myelofibrosis and understand the cellular and molecular makeup of the diseased microenvironment. We aim to understand the composition and alteration of the bone marrow microenvironment in myelofibrosis. This may provide novel therapeutic targets for myelofibrosis.
This project explores the connection between the niche – the area in the bone marrow where blood cells are formed – and the development of leukemia stem cells (LSCs) that give way to primary myelofibrosis (PMF). PMF is a stem cell-derived blood malignancy with the characteristics of too many cells in the blood and a large amount of scar tissue formation (fibrosis) in the bone marrow. PMF often progresses to an aggressive acute myeloid leukemia, causing high mortality. Strategies aimed at eradicating disease-causing LSCs are the key to cure the disease. Current treatment options for PMF are limited, and the only potential cure, stem cell transplantation, is often prohibitively toxic for most patients. Scientists reported in 2005 that recurrent mutations resulting in abnormal activation of the JAK-STAT pathway are drivers of PMF and other related diseases. This ground-breaking discovery led to the development of FDA-approved drugs targeting JAK2, such as ruxolitinib. However, these inhibitors only reduce some symptoms without significant impact on reducing LSCs or mutant blood cells. Thus, a deeper understanding of the pathogenesis of PMF will offer new opportunity to better treat the disease. Blood-forming stem cells called hematopoietic stem cells (HSC), give rise to all mature blood cells. These cells are found in the bone marrow in a region called their “niche,” which is near the bone marrow vascular system. In the PMF diseased state, the fibrotic bone marrow niche is a critical component to PMF pathogenesis. We hypothesize that the abnormal bone marrow niche in PMF provides protection to disease-causing LSCs at the cost of the normal blood-forming HSCs. We further hypothesize that targeting the abnormal niche may help eliminate LSCs, preserve normal HSCs, and provide a potential cure to PMF. Our recent data show that bone marrow cells in the niche that express the Leptin receptor protein are the source of fibrosis via activation of a signaling network mediated by a protein called PDGFRa. We are elucidating the cellular and molecular mechanisms of how LSCs interact with the fibrotic niche in mouse models and how this negatively impacts normal HSCs. To explore the potential of translating our findings to the clinic, we will test whether targeting the PDGFRa pathway with a specific blocking antibody will lead to efficient elimination of LSCs. By having a deeper understanding of the interaction between LSCs and the niche, our strategy of targeting the diseased niche may provide novel therapeutics for PMF.