MicroRNAs are small non-coding RNAs that have recently become recognized as important molecular regulators in human cancer. However, despite the knowledge that microRNA expression is frequently deregulated in acute myeloid leukemia (AML), the role of microRNAs in the leukemic initiation and maintenance remains poorly understood, the understanding of which is our long-term goal. Following our previous work in trying to understand the role of microRNAs in hematopoiesis and in human cancers, here, we aim to understand the role of a specific microRNA family, the miR-125 family of microRNAs, in AML. We found that miR-125 family microRNAs display in vitro property associated with transformation in hematopoietic cells. Moreover, we have accumulated further evidence suggesting a role of these microRNAs in the leukemogenesis of AML. Through extensive microRNA expression profiling in human AMLs, we found a subgroup of AMLs display greatly elevated miR-125a or miR-125b levels. We also found that miR-125a expression is high in self-renewing hematopoietic stem cells (HSCs). Forced expression of miR-125a positively modifies stem cell activity and antagonizes the apoptotic pathway. In addition to our own work, it has been reported that miR-125b-1 is translocated in a subgroup of human AMLs and myelodysplastic syndromes. The major goal of this proposal is to determine the roles of miR-125 family microRNAs in leukemic initiation and maintenance, through developing and analyzing mouse models and human cells.
In Specific Aim 1, we will use several mouse models to determine the role of miR- 125 family microRNAs in the initiation of pre-leukemic state and AML.
In Specific Aim 2, we propose to identify the cellular and molecular mechanisms by which miR-125 microRNAs deregulate normal hematopoiesis.
In Specific Aim 3, we will determine the role of miR-125 microRNAs in the maintenance of pre-leukemic and leukemic conditions in mouse models and in human cells. Collectively, the proposed research will advance our understanding of the role of microRNAs in leukemic initiation and maintenance by specifically addressing the role of miR- 125 family microRNAs in acute myeloid leukemia. Success of this work will lead to a refined appreciation of a group of prevalent fatal diseases on the basis of small RNAs, and could establish immediate targets for therapeutic intervention.

Public Health Relevance

Leukemia is one of the leading causes of cancer mortality. MicroRNAs, a type of small RNA molecules, have recently been identified and postulated as cellular regulators in leukemia. This proposal focuses on understanding the role of miRNAs in causing pre-leukemic disorders and leukemia, and in pre-leukemic and leukemic maintenance, which will lead to the appreciation of their potential as therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA149109-04
Application #
8608494
Study Section
Molecular and Cellular Hematology (MCH)
Program Officer
Mufson, R Allan
Project Start
2011-03-01
Project End
2016-02-29
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
4
Fiscal Year
2014
Total Cost
$310,939
Indirect Cost
$124,189
Name
Yale University
Department
Genetics
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Pan, Wen; Zhu, Shu; Qu, Kun et al. (2017) The DNA Methylcytosine Dioxygenase Tet2 Sustains Immunosuppressive Function of Tumor-Infiltrating Myeloid Cells to Promote Melanoma Progression. Immunity 47:284-297.e5
Liu, Jun; Guo, Bo; Chen, Zhuo et al. (2017) miR-125b promotes MLL-AF9-driven murine acute myeloid leukemia involving a VEGFA-mediated non-cell-intrinsic mechanism. Blood 129:1491-1502
Cheng, Jijun; Pan, Wen; Lu, Jun (2017) Dense sgRNA Library Construction Using a Molecular Chipper Approach. Bio Protoc 7:
Roden, Christine; Gaillard, Jonathan; Kanoria, Shaveta et al. (2017) Novel determinants of mammalian primary microRNA processing revealed by systematic evaluation of hairpin-containing transcripts and human genetic variation. Genome Res 27:374-384
Cheng, Jijun; Roden, Christine A; Pan, Wen et al. (2016) A Molecular Chipper technology for CRISPR sgRNA library generation and functional mapping of noncoding regions. Nat Commun 7:11178
Gonzalez-Martin, Alicia; Adams, Brian D; Lai, Maoyi et al. (2016) The microRNA miR-148a functions as a critical regulator of B cell tolerance and autoimmunity. Nat Immunol 17:433-40
Roden, Christine; Lu, Jun (2016) MicroRNAs in Control of Stem Cells in Normal and Malignant Hematopoiesis. Curr Stem Cell Rep 2:183-196
Guo, Yanwen; Liu, Jun; Elfenbein, Sarah J et al. (2015) Characterization of the mammalian miRNA turnover landscape. Nucleic Acids Res 43:2326-41
Guo, Yanwen; Mastriano, Stephen; Lu, Jun (2014) A high-throughput microRNA expression profiling system. Methods Mol Biol 1176:33-44
Rennie, William; Liu, Chaochun; Carmack, C Steven et al. (2014) STarMir: a web server for prediction of microRNA binding sites. Nucleic Acids Res 42:W114-8

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