miR-125b-2 is a potential oncomiR on human chromosome 21 in megakaryoblastic leukemia

Klusmann, Jan‐Henning; Li, Zhe; Böhmer, Katarina; Maroz, Aliaksandra; Koch, Mia Lee; Emmrich, Stephan; Godinho, Frank J.; Orkin, Stuart H.; Reinhardt, Dirk

doi:10.1101/gad.1856210

Cited by 211 publications

(230 citation statements)

References 51 publications

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“…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.…”

Section: Oncogenic Mirnasmentioning

confidence: 99%

“…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. 48 These xenografted mice developed B-ALL and T-ALL suggesting an active role for miR-125b in leukemogenesis.…”

Section: Oncogenic Mirnasmentioning

confidence: 99%

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MicroRNAs in acute leukemia: from biological players to clinical contributors

2011

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MicroRNAs (miRNAs) are involved in the management of hematopoiesis. As a consequence, miRNA dysregulation causes disruption of the hematopoietic system and leukemia may arise. We here comprehensively discuss miRNAs found discriminative for cytogenetic and molecular subtypes of acute leukemia. These miRNAs are either known miRNAs involved in leukemogenesis with proven tumor suppressor or oncogenic activities or are newly identified by high-throughput sequencing with yet unknown function. Furthermore, forces are outlined that drive aberrant miRNA function, which include genetic abnormalities (for example, deletions, translocations and mutations) and epigenetic aberrations (for example, aberrant DNA methylation or histone modifications). Interestingly, leukemia-silenced miRNAs can be re-expressed upon treatment with de-methylating agents. Targeting miRNA expression may serve a therapeutical role, albeit at present this way of targeted therapy is in its infancy. However, emerging knowledge about the biology of miRNAs in leukemia may result into a role for these miRNAs in the diagnosis and treatment of acute leukemia.

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Section: Oncogenic Mirnasmentioning

confidence: 99%

Section: Oncogenic Mirnasmentioning

confidence: 99%

MicroRNAs in acute leukemia: from biological players to clinical contributors

2011

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“…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).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2011

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MicroRNA-125b-1 (miR-125b-1) is a target of a chromosomal translocation t(11;14)(q24;q32) recurrently found in human B-cell precursor acute lymphoblastic leukemia (BCP-ALL). This translocation results in overexpression of miR-125b controlled by immunoglobulin heavy chain gene (IGH) regulatory elements. In addition, we found that six out of twenty-one BCP-ALL patients without t(11;14)(q24;q32) showed overexpression of miR-125b. Interestingly, four out of nine patients with BCR/ABL-positive BCP-ALL and one patient with B-cell lymphoid crisis that had progressed from chronic myelogenous leukemia overexpressed miR-125b. To examine the role of the deregulated expression of miR-125b in the development of B-cell tumor in vivo, we generated transgenic mice mimicking the t(11;14)(q24;q32) (El/miR-125b-TG mice). El/miR-125b-TG mice overexpressed miR-125b driven by IGH enhancer and promoter and developed IgM-negative or IgM-positive lethal B-cell malignancies with clonal proliferation. B cells obtained from the El/miR-125b-TG mice were resistant to apoptosis induced by serum starvation. We identified Trp53inp1, a proapoptotic gene induced by cell stress, as a novel target gene of miR-125b in hematopoietic cells in vitro and in vivo. Our results provide direct evidence that miR-125b has important roles in the tumorigenesis of precursor B cells.

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“…We and others have defined a central function of miR-125b in stem cell homeostasis and leukemogenesis (Klusmann et al 2010b;O'Connell et al 2010). In particular, we identified chromosome 21 (hsa21)-encoded miR-125b-2 to be highly up-regulated in acute megakaryoblastic leukemia (AMKL), especially in Down syndrome (DS) patients.…”

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confidence: 99%

miR-99a/100∼125b tricistrons regulate hematopoietic stem and progenitor cell homeostasis by shifting the balance between TGFβ and Wnt signaling

et al. 2014

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Although regulation of stem cell homeostasis by microRNAs (miRNAs) is well studied, it is unclear how individual miRNAs genomically encoded within an organized polycistron can interact to induce an integrated phenotype. miR-99a/100, let-7, and miR-125b paralogs are encoded in two tricistrons on human chromosomes 11 and 21. They are highly expressed in hematopoietic stem cells (HSCs) and acute megakaryoblastic leukemia (AMKL), an aggressive form of leukemia with poor prognosis. Here, we show that miR-99a/100~125b tricistrons are transcribed as a polycistronic message transactivated by the homeobox transcription factor HOXA10. Integrative analysis of global gene expression profiling, miRNA target prediction, and pathway architecture revealed that miR-99a/100, let-7, and miR-125b functionally converge at the combinatorial block of the transforming growth factor b (TGFb) pathway by targeting four receptor subunits and two SMAD signaling transducers. In addition, down-regulation of tumor suppressor genes adenomatous polyposis coli (APC)/APC2 stabilizes active b-catenin and enhances Wnt signaling. By switching the balance between Wnt and TGFb signaling, the concerted action of these tricistronic miRNAs promoted sustained expansion of murine and human HSCs in vitro or in vivo while favoring megakaryocytic differentiation. Hence, our study explains the high phylogenetic conservation of the miR-99a/100~125b tricistrons controlling stem cell homeostasis, the deregulation of which contributes to the development of AMKL.

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miR-125b-2 is a potential oncomiR on human chromosome 21 in megakaryoblastic leukemia

Cited by 211 publications

References 51 publications

MicroRNAs in acute leukemia: from biological players to clinical contributors

MicroRNAs in acute leukemia: from biological players to clinical contributors

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

miR-99a/100∼125b tricistrons regulate hematopoietic stem and progenitor cell homeostasis by shifting the balance between TGFβ and Wnt signaling

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