R35CA253127

Molecular and Cellular Regulation of Pre-Leukemic Stem Cells and Their Therapeutic Targeting - Abstract

Clinical outcome in MDS and AML has not significantly improved over the past 50 years, and cure rates remain below 15% in the majority of patients (~85%) who are over 55 years of age. Fundamentally novel approaches are urgently needed to improve our understanding of disease pathogenesis and to enable more effective therapeutic intervention.

Evidence over the past 10 years has shown that MDS and AML arise from preleukemic stem cells (prel-SC), preceding the formation of fully transformed leukemia stem cells (LSC). Recent work has uncovered considerable subclonal heterogeneity of prel-SC in MDS and AML and has indicated that stem cell subclonal complexity plays a key role in pathogenesis, progression, and therapeutic resistance. However, the molecular and cellular mechanisms governing these processes are still largely unknown.

Transcription factors (TF) have long been recognized as critical regulators of normal and malignant hematopoiesis. Specifically, in MDS and AML, transcriptional dysregulation is key to confer the pathognomonic features of cellular dysplasia and a myeloid differentiation block. Cell fate and differentiation decisions, as well as the induction of a myeloid bias at the stem cell and multipotent progenitor level, which is one of the earliest cellular properties detected in prel-SC, are governed by transcription factors.

In addition, our recent work has discovered an unexpected degree of transcription dynamics and plasticity in hematopoietic stem and progenitors, and that both transcriptional plasticity and transcriptional memory are dysregulated in prel-SC and LSC.

Our major research questions/goals are to understand stem cell subclonal dynamics and their regulation in the initiation and progression of MDS and AML, to identify and study mechanisms of transcriptional cooperativity in pre-leukemic stem cells and their therapeutic targeting, and to study transcription dynamics and prel-SC fate dysregulation at a single-cell and single-molecule resolution.

To accomplish these goals, we will utilize novel tools for stem cell subclonal analysis in patients, as well as newly developed longitudinal mouse genetic models of prel-SC progression to MDS and AML. In addition, we will leverage recent advances in our ability to directly target key transcription factors by novel first-in-class pharmacological inhibitors, as well as novel experimental tools for the study of transcription dynamics at a single-molecule level in primary stem/progenitor cells from murine models and patients.

Overall, our research will delineate the molecular regulation of pre-cancerous cell states in MDS and AML pathogenesis. This will enable their therapeutic targeting, in addition to the elimination of the fully-transformed leukemic clones. Such an approach holds the promise of achieving lasting remissions and potentially curing MDS and AML.

Our long-term vision is that, once we understand the early transformation-initiating mechanisms in pre-cancerous stem cells, it may even be possible to target such pre-cancerous states before the onset of overt leukemia and thus prevent transformation.

Albert Einstein College Of Medicine

TO PROVIDE FUNDAMENTAL INFORMATION ON THE CAUSE AND NATURE OF CANCER IN PEOPLE, WITH THE EXPECTATION THAT THIS WILL RESULT IN BETTER METHODS OF PREVENTION, DETECTION AND DIAGNOSIS, AND TREATMENT OF NEOPLASTIC DISEASES. CANCER BIOLOGY RESEARCH INCLUDES THE FOLLOWING RESEARCH PROGRAMS: CANCER CELL BIOLOGY, CANCER IMMUNOLOGY, HEMATOLOGY AND ETIOLOGY, DNA AND CHROMOSOMAL ABERRATIONS, TUMOR BIOLOGY AND METASTASIS, AND STRUCTURAL BIOLOGY AND MOLECULAR APPLICATIONS.

93.396 - Cancer Biology Research

National Cancer Institute (NCI) [HHS - NIH]

Bronx, New York 10461 United States

Single Zip Code

NCI Outstanding Investigator Award (R35 Clinical Trial Not Allowed) (PAR-20-278)

Amendment Since initial award the total obligations have increased 492% from $776,201 to $4,594,192.