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Blood. 2015 Jun 18;125(25):3937-48. doi: 10.1182/blood-2014-11-612507. Epub 2015 Mar 16.

ICL-induced miR139-3p and miR199a-3p have opposite roles in hematopoietic cell expansion and leukemic transformation.

Author information

1
Department of Hematology, Erasmus University Medical Center Cancer Institute, Rotterdam, The Netherlands;
2
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands;
3
Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands; and.
4
Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands; and Dutch Childhood Oncology Group, The Hague, The Netherlands.

Abstract

Interstrand crosslinks (ICLs) are toxic DNA lesions that cause severe genomic damage during replication, especially in Fanconi anemia pathway-deficient cells. This results in progressive bone marrow failure and predisposes to acute myeloid leukemia (AML). The molecular mechanisms responsible for these defects are largely unknown. Using Ercc1-deficient mice, we show that Trp53 is responsible for ICL-induced bone marrow failure and that loss of Trp53 is leukemogenic in this model. In addition, Ercc1-deficient myeloid progenitors gain elevated levels of miR-139-3p and miR-199a-3p with age. These microRNAs exert opposite effects on hematopoiesis. Ectopic expression of miR-139-3p strongly inhibited proliferation of myeloid progenitors, whereas inhibition of miR-139-3p activity restored defective proliferation of Ercc1-deficient progenitors. Conversely, the inhibition of miR-199a-3p functions aggravated the myeloid proliferation defect in the Ercc1-deficient model, whereas its enforced expression enhanced proliferation of progenitors. Importantly, miR-199a-3p caused AML in a pre-leukemic mouse model, supporting its role as an onco-microRNA. Target genes include HuR for miR-139-3p and Prdx6, Runx1, and Suz12 for miR-199a-3p. The latter genes have previously been implicated as tumor suppressors in de novo and secondary AML. These findings show that, in addition to TRP53-controlled mechanisms, miR-139-3p and miR-199a-3p are involved in the defective hematopoietic function of ICL-repair deficient myeloid progenitors.

PMID:
25778535
DOI:
10.1182/blood-2014-11-612507
[Indexed for MEDLINE]
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