Identification of Mir-145 and Mir-146a as Micrornas Involved in the Pathogenesis of 5q- Syndrome

Deletion of the long arm of chromosome 5 is the most common cytogenetic alteration in myelodysplastic syndromes and is classified as a distinct subtype of the disease (5q- syndrome). Patients with 5q- syndrome present with macrocytic anemia, variable neutropenia, normal or elevated platelet counts, and megakaryocyte dysplasia. Over time these patients progress to marrow failure or acute myeloid leukemia. The commonly deleted region in 5q- syndrome contains numerous genes that are implicated in hematopoiesis, however no single gene loss recapitulates all features of 5q- syndrome in vivo. We examined the expression of microRNAs (miR) within the deleted region of chromosome 5q and found reduced expression of miR-145 and miR-146a in patients with del (5q). Knockdown of miR-145 or miR-146a in normal mouse hematopoietic cells resulted in increased megakaryopoiesis. We identified TIRAP and TRAF6 as critical mRNA targets of miR-145 and miR-146a, respectively. Expression of TIRAP alone resulted in autoactivation of TRAF6, implicating activation of a common pathway with loss of either miR-145 or miR-146a. Transplantation of lethally-irradiated mice with marrow cells expressing retrovirally-transduced TRAF6 resulted in neutropenia, anemia, thrombocytosis, and hypolobulated megakaryocytes. Long-term follow up of chimeric mice over 12 months revealed progression in approximately half the mice to marrow failure or acute leukemia. Further experiments revealed that recapitulation of 5q- syndrome-like features were mediated by paracrine effects induced by IL-6, as well as by cell autonomous TRAF6 effects. These findings suggest that several of the features of 5q- syndrome may be secondary to loss of microRNAs within the deleted region of chromosome 5q.