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Loss of miR-143 and miR-145 inhibits hematopoietic stem cell self-renewal via dysregulated TGF-beta signaling

University of British Columbia

Myelodysplastic syndromes (MDS) are a collection of hematopoietic malignancies in which genomic abnormalities within the hematopoietic stem cell (HSC) compartment lead to pancytopenia and eventual bone marrow failure or progression to leukemia. The most common karyotypic abnormality in MDS is the interstitial deletion of chromosome 5q where a commonly deleted region (CDR) has been identified. Two microRNAs (miRNA) located within the CDR have been shown to be expressed at lower levels in del(5q) MDS compared to diploid MDS. Here I describe investigations of the functional consequence of loss of these two miRNAs, miR-143 and miR-145, on hematopoietic stem and progenitor cells. Loss of miR-143/145 in mice resulted in a decrease in hematopoietic stem cells and myeloid progenitors. I also identified a direct link between the loss of miR-143/145 and subsequent activation of both the canonical and non-canonical transforming growth factor beta (TGFβ) signaling pathways, mediated in part via the adaptor protein, Disabled-2 (DAB2). Analysis of del(5q) MDS patient bone marrow revealed an enriched TGFβ-signature compared to healthy controls and we show that TGFβ signaling is activated upon loss of miR-145 or enforced expression of its target, DAB2. Subsequent studies focused on the function of DAB2 within the hematopoietic system. Overexpression of DAB2 in mouse bone marrow resulted in a significant decrease in hematopoietic stem cell frequency, self-renewal, and colony forming activity. In competitive transplants, vector-transduced bone marrow cells were able to outcompete DAB2-overexpressing marrow in both primary transplants as well as in secondary limiting dilution assays. However, a subset of mice with enforced DAB2 expression alone developed a transplantable acute myeloid leukemia. In conclusion, our data suggest a role for miR-145 haploinsufficiency in the inappropriate activation of TGFβ signaling through derepression of DAB2 which leads to abnormal HSC function in del(5q) MDS.

Text

2016-01-05

Attribution-NonCommercial-NoDerivs 2.5 Canada

http://hdl.handle.net/2429/56229

Interdisciplinary Oncology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/2.5/ca/