Hsa-mir-125b-2 is highly expressed in childhood ETV6/RUNX1 (TEL/AML1) leukemias and confers survival advantage to growth inhibitory signals independent of p53

Abstract

MicroRNAs (miRNAs) regulate the expression of multiple proteins in a dose dependent manner. We hypothesized that increased expression of miRNAs encoded on chromosome 21 (chr 21) contribute to the leukemogenic role of trisomy 21. The levels of chr 21 miRNAs were quantified by qRT-PCR in four types of childhood ALL characterized by either numerical (trisomy or tetrasomy) or structural abnormalities of chr 21. Suprisingly high expression of the hsa-mir-125b-2 cluster, consisting of three miRNAs, was identified in leukemias with the structural ETV6/RUNX1 abnormality and not in ALLs with trisomy 21. Manipulation of ETV6/RUNX1 expression and chromatin immunoprecipitation studies demonstrated that the high expression of the miRNA cluster is an event independent of the ETV6/RUNX1 fusion protein. Overexpression of hsa-mir-125b-2 conferred a survival advantage to Ba/F3 cells following IL-3 withdrawal or a broad spectrum of apoptotic stimuli through inhibition of caspase 3 activation. Conversely, knockdown of the endogenous miR-125b in the ETV6/RUNX1 leukemia cell line REH increased apoptosis after Doxorubicin and Staurosporine treatments. P53 protein levels were not altered by miR-125b. Together these results suggest that the expression of hsa-mir-125b-2 in ETV6/RUNX1 ALL provides survival advantage to growth inhibitory signals in a p53 independent manner.

MicroRNAs in acute leukemia: from biological players to clinical contributors

“…22 Functional studies showed that inhibition of miR-125b sensitized TEL-AML1-positive cells to doxorubicin. 24 These studies exemplify a role for miR-125b in leukemogenesis and points to miR-125b as potential therapeutic target.…”

“…35 MiR-125b and neighboring miRNA genes let-7c, miR-99a and miR-100 were aberrantly upregulated in TEL-AML1-positive ALL and different myeloid leukemias (Tables 1 and 2). 24,46,47 Pro-B cells gained a survival advantage 24 and differentiation of CD34 þ myeloid progenitors was disturbed upon miR-125b overexpression. 46,47 Moreover, the oncogenic activity of miR-125b was recently shown in mice, which were transplanted with fetal liver cells that overexpressed miR-125b.…”

“…49 Enforced expression of miR-125b also facilitated IL3-independent growth of Ba/F3 mouse cells. 24 In addition to its oncogenic role, miR-125b expression has been associated with drug resistance in TEL-AML1-positive pediatric ALL. 22 Functional studies showed that inhibition of miR-125b sensitized TEL-AML1-positive cells to doxorubicin.…”

Eμ/miR-125b transgenic mice develop lethal B-cell malignancies

“…5,6 An evolutionally conserved miRNA, miR-125b, has been implicated in human cancers. [7][8][9][10][11][12] MiR-125b-1, mapped on 11q24, has been found to be a target of recurrent chromosomal abnormalities seen in both lymphoid and myeloid malignancies. [7][8][9][10] We previously reported an insertion of miR-125b-1 into the IGH locus in a patient with B-cell precursor acute lymphoblastic leukemia (BCP-ALL).…”

MicroRNA miR-125b causes leukemia

“…Thus, we show that overexpression of miR-125b is sufficient both to shorten the latency of BCR-ABL-induced leukemia and to independently induce leukemia in a mouse model. M icroRNAs are a family of small noncoding RNA (18)(19)(20)(21)(22)(23)(24)(25) nucleotides) that act as crucial posttranscriptional regulators of genes involved in many fundamental process, including differentiation, proliferation, and apoptosis (1,2).…”