Cellular and molecular basis of microRNA-29a induced acute myeloid leukemia. Acute myeloid leukemia (AML) arises from the accumulation of genetic and/or epigenetic changes in immature hematopoietic cells. While leukemogenesis involves multiple steps including initiation, progression, transformation, and maintenance, studying these processes in human disease presents many practical challenges;however, well-characterized mouse models of AML afford the opportunity to study each of them due to the relative ease of genetically modifying cells and testing cellular function in a variety of in vitroand in vivo assays. While AML arises from immature hematopoietic cells, the exact cell that initiates disease or ultimately transforms into the leukemia stem cell (LSC) is unclear. We previously showed that microRNA-29a (miR-29a) is highly expressed in human HSC and AML LSC, and that ectopic expression of miR-29a in mouse BM cells is sufficient to induce a myeloproliferative neoplasm (MPN)-like disease that progresses to AML. We characterized miR-29a induced disease and showed that self-renewing committed progenitors arise prior to the development of AML and that miR-29a induced AMLs contain LSCs that can be prospectively isolated based on the expression of specific cell surface markers. Although the precise role of the self-renewing progenitors has not been defined, their appearance raises the intriguing possibility that aberrant acquisition of self-renewal by committed progenitors may be an early event in AML pathogenesis. Overall, these data demonstrate that the miR-29a induced AML model is a robust and experimentally tractable model for studying AML pathogenesis. We propose to characterize miR-29a's roles during AML development and to elucidate the molecular basis of miR-29a's regulation of self-renewal in LSCs and aberrantly self-renewing progenitors. We will determine if miR-29a is required for leukemogenesis utilizing our newly developed miR-29a deficient mouse model as well as various mouse models of AML. We will identify the cell population/s that become transformed during miR- 29a driven leukemogenesis, and we will also test the contribution of two miR-29a targets, Dnmt3a and Smpd3 (genes also recurrently mutated in human AML) to miR-29a induced phenotypes. To identify potential genes or mutations that may cooperate with miR-29a to induce leukemia, we will perform RNA-Seq on LSCs and aberrantly self-renewing progenitors. Finally, we will leverage our experience working with the miR-29a induced AML model as well as with primary human AML samples to evaluate the role of miR-29a in LSC function in the serial transplantation setting, the gold-standard assay for self-renewal. Ultimately, we expect these studies to generate new insights into the role of miR-29a in AML, define the molecular mechanisms of miR-29a's actions in pre-leukemic intermediates (including the molecular basis for self-renewal), and determine whether miR-29a or its downstream mediators may serve as potential therapeutic targets in AML.

Public Health Relevance

Acute myeloid leukemia (AML) is a difficult-to-treat cancer with poor clinical outcomes that results from the accumulation of genetic and epigenetic changes in the most immature blood cells. We will determine the requirement for microRNA-29a in AML development and elucidate the molecular basis of microRNA-29a's leukemogenic activity, especially in leukemic stem cells, which maintain disease and thus must be eliminated to effect cure. We expect that our studies will define miR-29a's role in AML development, identify the cells that become leukemic stem cells, elucidate the molecular mechanisms underlying the various transitions during disease development, and determine whether miR-29a or its downstream mediators are viable novel therapeutic targets.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Molecular and Cellular Hematology (MCH)
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Mufson, R Allan
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Khalaj, Mona; Woolthuis, Carolien M; Hu, Wenhuo et al. (2017) miR-99 regulates normal and malignant hematopoietic stem cell self-renewal. J Exp Med :
Ye, Haobin; Adane, Biniam; Khan, Nabilah et al. (2016) Leukemic Stem Cells Evade Chemotherapy by Metabolic Adaptation to an Adipose Tissue Niche. Cell Stem Cell 19:23-37
Hu, Wenhuo; Dooley, James; Chung, Stephen S et al. (2015) miR-29a maintains mouse hematopoietic stem cell self-renewal by regulating Dnmt3a. Blood 125:2206-16
Hu, Wenhuo; Park, Christopher Y (2014) Measuring microRNA expression in mouse hematopoietic stem cells. Methods Mol Biol 1185:121-40