Friday, April 25, 2025
4/25/2025
Genes regulating stem and progenitor cell expansion and relapse in Acute Myeloid Leukemia - Acute myelogenous leukemia (AML) is diagnosed in 21,450 adult patients in the US per year with a five-year survival rate of 29%. Standard AML therapy comprises chemotherapy induction to achieve leukemia cytoreduction, followed by cycles of consolidation chemotherapy alone and/or followed by allogeneic bone marrow transplantation. This general therapeutic approach to AML is risk-adapted relying principally on well- established pre-treatment prognostic factors, including the type of AML, age, gene mutations and cytogenetic results. A fundamental barrier to AML cure is therapy resistance and disease relapse despite achieving a clinical complete remission (CR) following standard chemotherapy regimens. Of high interest, therefore, is the identification of cellular and molecular mechanisms that underlie persistence and competitive regrowth of leukemic cells after therapy. These persistent cells expand and give rise to full blown AML at clinical relapse. The long-term hematopoietic stem cells (LT-HSCs) acquire mutations that allow for competitive growth advantages on a continuum from clonal hematopoiesis to pre-leukemic stem cells (pre-LSC) to leukemic stem cells as documented for DNMT3A, TET2 and other genes, and are also the target for additional changes that ultimately constitute the various leukemia phenotypes. While most work in this area has focused on cooperating gene mutations, there likely exist multiple unidentified mechanisms and paths of transforming a pre-LSC to a leukemia cell, and multiple genes that can confer growth advantages on leukemia cells in various disease phases. In particular, the genes and pathways underlying AML relapse remain poorly characterized but are central to improvements in AML therapy. Therefore, the complexity and phenotypic diversity of human AML is not determined by single gene effects or mutations and a working model based on multi gene effects is likely more productive. Our basic hypothesis underlying this proposal is that AML cell populations as a quasi species have sufficient phenotypic diversity to select from multiple novel deregulated genes in parallel as drivers of leukemia relapse. We have identified a candidate gene pool of such novel genes that influence normal and leukemic stem and progenitor expansion, and these genes will be studied in-depth in this proposal. The resistance to chemotherapy remains a major roadblock to AML cure. The underlying mechanisms are multiple and only partially understood. Using a candidate gene pool identified from scRNA-seq and CRISPR screens in primary human AML, we will study and validate novel genes as modifiers of the response to daunorubicin in AML and their contributions to AML relapse. In summary, our innovative studies aim at functional validation of novel gene drivers underlying therapy resistance and competitive acute leukemia cell regrowth at relapse.
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