MicroRNA-29a and microRNA-142-3p are regulators of myeloid differentiation and acute myeloid leukemia

Abstract

IntroductionAcute myeloid leukemia (AML) is a heterogeneous group of blood cancers characterized by increased, uncontrolled proliferation of hematopoietic progenitors, and a blockage in myeloid differentiation is the major characteristic of AML. 1 According to the French-American-British classification system, AMLs involving the monocytic and granulocytic lineage account for 85% (M1 to M5 subtypes) of adult patients. 2 Under normal conditions, monocytes and granulocytes develop from long-term hematopoietic stem cells (LT-HSCs) in BM under the influence of a complex network of cytokins such as G-CSF, GM-CSF, and M-CSF, and transcription factors such as PU.1, C/EBP, IFN consensus sequence binding protein/IFN regulatory factor 8, Krüppel-like factor 4, c-Maf, and C/EBP⑀. [3][4][5][6] MicroRNAs (miRNAs) that negatively regulate gene expression at posttranscriptional level 7 have also been identified as crucial regulators in normal and malignant myeloid differentiation. Expression and function analyses have unraveled their important regulatory roles during hematopoiesis. 8 In a previous study, we demonstrated a significantly decreased expression of miR-29a and 142-3p in the peripheral blood mononuclear cells (PBMNCs) from AML patients (French-AmericanBritish M1 to M5 subtypes). 9 These 2 miRNAs were also reported to be down-regulated in a variety of tumors and to act as tumor suppressors. [10][11][12] The miR-29a cluster is one of the most studied miRNA clusters. Down-regulation of miR-29a was observed in AML samples with deletions of 7q (del7q). 10 Several genes have been reported to be silenced by miR-29, most of which are potential oncogenes, such as SKI, Tcl1, the p53 upstream inhibitors p85a and CDC42, and the Bcl2 family members Bcl2 and Mcl1. 11 Meanwhile, miR-142-3p, first identified as being uniquely expressed in hematopoietic system, is aberrantly expressed in T-cell and B-cell leukemia. 12 In addition, increased miR-142-3p expression has been observed at different stages of normal granulocytopoiesis. 13 Validated targets of miR-142-3p include ADCY9, 14 CD133, 16 and the RAC1. 17 In this study, we sought to investigate role of these 2 miRNAs in monocytic and granulocytic differentiation (also called myeloid differentiation), and to test whether their down-regulation is related to the differentiation block in AML blasts. Using the leukemia cell lines, NB4, HL-60, and THP-1 18-23 we observed up-regulation of miR-29a and miR-142-3p expression during all-trans-retinoic acid (ATRA)-induced granulocytic differentiation and phorbol 12-myristate 13-acetate (PMA)-induced monocytic differentiation, and examined effects of overexpression or knockdown of each miRNA on myeloid differentiations. Moreover, we identified targets of both miRNAs and examined direct effect of the target genes on myeloid differentiation. Similar results were also obtained in myeloid induction cultures of CD34 ϩ hematopoietic stem/ progenitor cells (HSPCs) derived from normal human umbilical cord blood (UCB) and BM from healthy donors and AML p...

The role of miR-29 family members in malignant hematopoiesis

“…Prognostic value of miR-29a expression was especially more obvious in the subgroup of patients with intermediate risk cytogenetics 3 . This finding is consistent with the previous study showing reduced expression of miR-29a in adult AML patients 99 . In addition it was found that the decreased expression of miR-29a was significantly associated with classification subtype M7 (FAB) and the unfavorable cytogenetic risks 3 .…”

“…It is conceivable that miR-29a and miR-142-3p promote myeloid differentiation primarily by affecting CCNT2, CDK6 and TAB2. Significantly increased levels of the target proteins were detected in the AML blast with abnormally reduced expression of miR-29a and miR-142-3p, which further suggested that these two miRNAs regulate myeloid differentiation and AML development via the three target genes 98,99 . Experimental data indicated that forced expression of miR-29a and miR-29b in AML cell lines and in primary AML blasts inhibited cell growth and induced apoptosis.…”

miR-142-3p regulates the formation and differentiation of hematopoietic stem cells in vertebrates

“…Later studies using mouse and human cell lines have indicated that miR-142-3p is required for the development and function of terminally differentiated hematopoietic lineages, such as myeloid and dendritic cells. miR-142-3p can directly regulate the expression of tab2 in the myeloid lineage [22] and that of IL-6 in dendritic cells(DCs) [23]. Very recently, zebrafish miR-142-3p (ZFIN ID: ZDB-GENE-090929-151, miR-142a-3p herein) has been shown to be required for the maturation of primitive erythrocytes, cardiogenesis and vessel integrity [24,25].…”

miR-29 Promotes Murine Osteoclastogenesis by Regulating Osteoclast Commitment and Migration

“…We considered that miR-29 family members may also play a role in osteoclastogenesis, given that altered miR-29 levels were associated with hematopoietic malignancies. For example, diminished miR-29 levels were found in patients with chronic lymphocytic leukemia and correlate with advanced clinical features and poor prognosis in acute myeloid leukemia (23)(24)(25)(26).…”