The c-myb proto-oncogene and microRNA-15a comprise an active autoregulatory feedback loop in human hematopoietic cells

Zhao, Helen; Kalota, Anna; Jin, Shenghao; Gewirtz, Alan M.

doi:10.1182/blood-2008-01-136218

Cited by 148 publications

(130 citation statements)

References 50 publications

(51 reference statements)

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“…1C). Recent studies have demonstrated that MYB is a major target of these miRNAs and that they negatively regulate MYB expression through these binding sites (18)(19)(20)(21).…”

Section: Resultsmentioning

confidence: 99%

Recurrent fusion of MYB and NFIB transcription factor genes in carcinomas of the breast and head and neck

Persson

Andrén

Mark

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

712

639

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The transcription factor gene MYB was identified recently as an oncogene that is rearranged/duplicated in some human leukemias. Here we describe a new mechanism of activation of MYB in human cancer involving gene fusion. We show that the t(6;9)(q22-23;p23-24) translocation in adenoid cystic carcinomas (ACC) of the breast and head and neck consistently results in fusions encoding chimeric transcripts predominantly consisting of MYB exon 14 linked to the last coding exon(s) of NFIB. The minimal common part of MYB deleted as the result of fusion was exon 15 including the 3 -UTR, which contains several highly conserved target sites for miR-15a/16 and miR-150 microRNAs. These microRNAs recently were shown to regulate MYB expression negatively. We suggest that deletion of these target sites may disrupt repression of MYB leading to overexpression of MYB-NFIB transcripts and protein and to activation of critical MYB targets, including genes associated with apoptosis, cell cycle control, cell growth/angiogenesis, and cell adhesion. Forced overexpression of miR-15a/16 and miR-150 in primary fusion-positive ACC cells did not significantly alter the expression of MYB as compared with leukemic cells with MYB activation/duplication. Our data indicate that the MYB-NFIB fusion is a hallmark of ACC and that deregulation of the expression of MYB and its target genes is a key oncogenic event in the pathogenesis of ACC. Our findings also suggest that the gain-offunction activity resulting from the MYB-NFIB fusion is a candidate therapeutic target.chromosome translocation ͉ fusion oncogene ͉ miRNA ͉ adenoid cystic carcinoma F usion genes are potent oncogenes resulting from chromosome rearrangements, in particular translocations. Most fusion genes identified thus far have been in hematological disorders and mesenchymal neoplasms, and only a few have been found in carcinomas (1). This paucity probably results from an inability to discover these rearrangements rather than from a true lack of such genes in carcinomas. The recent discovery that the majority of prostate cancers harbor ETS gene fusions (2) is in line with this reasoning. Finding as yet unidentified fusion oncogenes in other carcinomas could provide important insights into the molecular pathogenesis of these cancers and also might facilitate the development of new targeted therapies.We previously have identified a recurrent and tumor-specific t(6;9)(q22-23;p23-24) translocation in adenoid cystic carcinoma (ACC) of the head and neck (3). The translocation has been found as the sole cytogenetic anomaly in several cases, indicating that it is a primary rearrangement in this carcinoma.ACC has been known as a histologically distinctive neoplasm for nearly 150 years. It is among the most common carcinomas of the salivary glands (4) but also may arise in other exocrine glands, such as in the breast, and in the cervix, vulva, and tracheobronchial tree (5). ACC usually is an aggressive, although slowly growing, cancer with a long-term poor prognosis. Most patients (80-90%) with ACC ...

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“…1C). Recent studies have demonstrated that MYB is a major target of these miRNAs and that they negatively regulate MYB expression through these binding sites (18)(19)(20)(21).…”

Section: Resultsmentioning

confidence: 99%

Recurrent fusion of MYB and NFIB transcription factor genes in carcinomas of the breast and head and neck

Persson

Andrén

Mark

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

712

639

View full text Add to dashboard Cite

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“…5 Genetic alterations involving MYB, including locus duplication, were earlier found in a subset of T-acute lymphoblastic leukemia. 6 In addition, Zhao et al 7 recently reported on a negative feedback loop between MYB and miR-15a located in 13q14, a region frequently deleted in myeloid and lymphocytic leukemia. Thus, MYB is an interesting candidate for leukemic transformation that may co-operate with heterozygous germline mutations in RUNX1 and del(5q).…”

Section: Referencesmentioning

confidence: 99%

“…Exclusion criteria included marrow findings as below, and the usual contraindications to recombinant interferon alpha-2b (rIFNa). 7 The bone-marrow biopsy specimens, routinely processed, were stained with hematoxylin-eosin and giemsa, and for reticulin and collagen, quantified by the method of Manoharan, et al 6 Excluded patients showed advanced fibro-osteosclerosis, grade 3 or 4 reticulin deposition, coarse bundles of collagen fibers 6 and no residual hematopoiesis. Patients considered for study required…”

Section: Referencesmentioning

confidence: 99%

A novel pedigree with heterozygous germline RUNX1 mutation causing familial MDS-related AML: can these families serve as a multistep model for leukemic transformation?

et al. 2009

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phenotype nor a clear-cut genetic background has been observed in these studies. Syampurnawati et al. 9 described cases with AML M1/M2 lacking the expression of HLA-DR in which NPM1 mutations were observed in 69%. Thus, a relation to the molecular genetic aberration, that is NPM1 mutation, was found; however, again the correlation was not complete and no comprehensive immunophenotype was described.The previously described cup-like morphology has been reported to be associated with NPM1 mutations, 4 with FLT3-ITD and with a lack of HLA-DR expression; 10 however, again no complete correlations were observed.A variety of reports has been published on AML with NPM1 mutations describing cytomorphologic characteristics (high frequency of AML M4/M5), the lack of recurrent genetic abnormalities, and a high frequency of myelomonocytic immunophenotypes as well as an infrequent expression of CD34 5,11 which led to 'AML with mutated NPM1' being included as a provisional entity in the 2008 WHO classification of tumors of hematopoietic and lymphoid tissues. 12 The report of the present series adds on these data by providing a subgroup of AML cases with NPM1 type A mutations which display a unique and homogeneous immunophenotype. It should be noted, however, that these cases comprise a subgroup only of all AML with NPM1 type A mutations. Taking into consideration previously described leukemia subtypes, which were identified by homogeneous immunophenotypes correlated with cytomorphologic features and in which disease-defining genetic alteration subsequently were identified, the present data may be considered the basis to suggest the presence of a homogeneous genetic background in these cases. Following the two-hit model of pathogenesis of AML as suggested by Gilliland et al. 13 and considering that only the NPM1 type A mutation was consistently found in the present cases a second consistently present and not yet identified mutation may be postulated. Therefore, the present subgroup of AML with NPM1 type A mutation provides an ideal target for further research on the mechanism of leukemogenesis.

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“…miR-15a/144/451 regulate erythropoiesis and miR-223 is key to granulocytic differentiation. [11], [12], [13] AML is a heterogeneous leukemic disease affecting the myeloid lineage and characterized by a block of differentiation at different stages of myelopoeisis. [14] According to the French-AmericanBritish (FAB) classification AML can be classified into eight subtypes based on their blast cell morphology.…”

Section: Introductionmentioning

confidence: 99%

The RNA binding proteins RBM38 and DND1 are repressed in AML and have a novel function in APL differentiation

et al. 2016

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The RNA binding proteins RBM binding motif protein 38 (RBM38) and DEAD END 1 (DND1) selectively stabilize mRNAs by attenuating RNAse activity or protecting them from micro(mi)RNA-mediated cleavage. Furthermore, both proteins can efficiently stabilize the mRNA of the cell cycle inhibitor p21 CIP1 . Since acute myeloid leukemia (AML) differentiation requires cell cycle arrest and RBM38 as well as DND1 have antiproliferative functions, we hypothesized that decreased RBM38 and DND1 expression may contribute to the differentiation block seen in this disease. We first quantified RBM38 and DND1 mRNA expression in clinical AML patient samples and CD34 + progenitor cells and mature granulocytes from healthy donors. We found significantly lower RBM38 and DND1 mRNA levels in AML blasts and CD34 + progenitor cells as compared to mature neutrophils from healthy donors. Furthermore, the lowest expression of both RBM38 and DND1 mRNA correlated with t(8;21). In addition, neutrophil differentiation of CD34 + cells in vitro with G-CSF (granulocyte colony stimulating factor) resulted in a significant increase of RBM38 and DND1 mRNA levels. Similarly, neutrophil differentiation of NB4 acute promyelocytic leukemia (APL) cells was associated with a significant induction of RBM38 and DND1 expression. To address the function of RBM38 and DND1 in neutrophil differentiation, we generated two independent NB4_RBM38 as well as DND1 knockdown cell lines. Inhibition of both RBM38 and DND1 mRNA significantly attenuated NB4 differentiation and resulted in decreased p21 CIP1 mRNA expression. Our results clearly indicate that expression of the RNA binding proteins RBM38 and DND1 is repressed in primary AML patients, that neutrophil differentiation is dependent on increased expression of both proteins, and that these proteins have a critical role in regulating p21 CIP1 expression during APL differentiation. Highlights RBM38 and DND1 expression is attenuated in primary AML patients  Normal and leukemic neutrophil differentiation induces RBM38 and DND1 expression  New function for the RNA binding proteins RBM38 and DND1 in APL differentiation Keywords: RBM38, DND1, acute myeloid leukemia, acute promyelocytic leukemia, neutrophil differentiation

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The c-myb proto-oncogene and microRNA-15a comprise an active autoregulatory feedback loop in human hematopoietic cells

Cited by 148 publications

References 50 publications

Recurrent fusion of MYB and NFIB transcription factor genes in carcinomas of the breast and head and neck

Recurrent fusion of MYB and NFIB transcription factor genes in carcinomas of the breast and head and neck

A novel pedigree with heterozygous germline RUNX1 mutation causing familial MDS-related AML: can these families serve as a multistep model for leukemic transformation?

The RNA binding proteins RBM38 and DND1 are repressed in AML and have a novel function in APL differentiation

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