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Therapeutically actionable molecular safeguards in leukemic stem cells

Dr. Will

Britta Will


Albert Einstein College of Medicine

Project Term: July 1, 2023 - June 30, 2028

Our research program’s goal is to identify therapeutically actionable pathways in pre-leukemic and leukemic stem cells in myeloid malignancies. We specifically dissect molecular circuits governing stem cell self-renewal and differentiation, how these change during aging, and contribute to leukemic stem cell evolution and maintenance. Accomplishing this work will enable the rational design of curative intervention and perhaps even prevention strategies for patients with myeloid malignancies.

Lay Abstract

Blood-forming (hematopoietic) stem cells (HSC) are bone marrow-resident and in charge of the life-long production of our highly diverse blood cell supply enabling oxygen transport, coagulation, wound healing, and immunity. These highly potent adult stem cells are also the origin of poorly curable blood cancers - particularly aging-associated myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). While MDS and AML are clinically and molecularly diverse diseases, they arise from abnormal (“transformed”) HSC, or leukemic stem cells (LSC) which share biological hallmarks of abnormal regeneration and inability to fully mature to functioning blood cells through differentiation. LSC, typically spared by conventional therapy, produce aggressively growing immature “blast” cells which severely compromise healthy blood formation and drive disease progression and relapse. Our incomplete understanding of the molecular mechanisms, particularly gene regulation, endowing HSC with their unique functional repertoire stands in the way of fundamentally new and curative therapies which necessitate elimination of LSC. While great efforts have been devoted to understanding how acquired gene variations (“DNA mutations”) altering protein function may drive MDS and AML, much less focus has been on gene regulatory and non-genetic molecular mechanisms. Our past and ongoing work has for the first time established central roles of iron- and highly selective protein recycling-regulated pathways in sustaining healthy HSC function. Moreover, through employing clinically relevant models of healthy hematopoiesis, MDS and AML paired with cutting-edge molecular assays and data mining, we have discovered a gene network dependent on hematopoietic master regulator PU.1 which protects HSC from leukemic transformation. Our current and future research aims at expanding our insights into how aging leads to cellular iron accumulation and the decline in protein recycling, how these perturbations predispose HSC to cancerous transformation, and evaluating the efficacy and safety of pharmacologic agents restoring iron balance and protein recycling for targeting LSC. If successful, this work will uncover new biomarkers for early detection of and enable LSC-directed therapeutic targeting in MDS and AML.

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