RBM15-MKL1 (OTT-MAL) fusion transcript in an adult acute myeloid leukemia patient

Hsiao, Hui‐Hua; Yang, Mingyu; Liu, Yi-Chang; Hsiao, Hui‐Pin; Tseng, Shih-Bin; Chao, Mei-Chyn; Liu, Ta-Chih; Lin, Sheng-Fuu

doi:10.1002/ajh.20298

Cited by 17 publications

(9 citation statements)

References 12 publications

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“…The C-terminal portion of the C11orf95-MKL2 chimeric protein contains a SAP DNA-binding domain, a coiled-coiled (CC) domain and a proline-rich region known to be present in transcription factors and oncoproteins. Interestingly, a rearrangement involving another MKL gene family member ( MKL1 ) has been identified in t(1;22)(p13;q13) acute megakaryoblastic leukemia (Ma et al, 2001; Cen et al, 2003) and t(1;22)(p13;q13) acute myeloid leukemia, subtype M1 ( Hsiao et al, 2005). This translocation results in a fusion of RBM15 and MKL1 that also encompasses all putative functional motifs encoded by each gene.…”

Section: Discussionmentioning

confidence: 99%

C11orf95‐MKL2 is the resulting fusion oncogene of t(11;16)(q13;p13) in chondroid lipoma

Huang

Sümegi

Cin

et al. 2010

Genes Chromosomes & Cancer

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Chondroid lipoma, a rare benign adipose tissue tumor, may histologically resemble myxoid liposarcoma or extraskeletal myxoid chondrosarcoma, but is genetically distinct. In the current study, an identical reciprocal translocation, t(11;16)(q13;p13) was identified in three chondroid lipomas, a finding consistent with previous isolated reports. A fluorescence in situ hybridization (FISH)-based positional cloning strategy using a series of bacterial artificial chromosome (BAC) probe combinations designed to narrow the 16p13 breakpoint revealed MKL2 as the candidate gene. Subsequent 5′ RACE studies demonstrated C11orf95 as the MKL2 fusion gene partner. MKL/myocardin-like 2 (MKL2) encodes myocardin-related transcription factor B (MRTF-B) in a megakaryoblastic leukemia gene family, and C11orf95 (chromosome 11 open reading frame 95) is a hypothetical protein. Sequencing analysis of RT-PCR generated transcripts from all three chondroid lipomas defined the fusion as occurring between exons 5 and 9 of C11orf95 and MKL2, respectively. Dual-color breakpoint spanning probe sets custom-designed for recognition of the translocation event in interphase cells confirmed the anticipated rearrangements of the C11orf95 and MKL2 loci in all cases. The FISH and RT-PCR assays developed in this study can serve as diagnostic adjuncts for identification of this novel C11orf95-MKL2 fusion oncogene in chondroid lipoma.

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Section: Discussionmentioning

confidence: 99%

C11orf95‐MKL2 is the resulting fusion oncogene of t(11;16)(q13;p13) in chondroid lipoma

Huang

Sümegi

Cin

et al. 2010

Genes Chromosomes & Cancer

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“…Cold Spring Harbor Laboratory Press on May 10, 2018 -Published by genesdev.cshlp.org Downloaded from fused with the gene encoding One-twenty-two (OTT/ RBM15), a putative RNA-binding protein (Mercher et al 2001Dastugue et al 2002Hrusak and PorwitMacDonald 2002;Ballerini et al 2003;Duchayne et al 2003;Gilliland et al 2004;Hsiao et al 2005). The resulting RBM15-MRTF-A fusion protein contains almost the entire OTT protein sequence fused near the N terminus of MRTF-A, after the first predicted RPEL domain.…”

Section: Genes and Development 1551mentioning

confidence: 99%

The myocardin family of transcriptional coactivators: versatile regulators of cell growth, migration, and myogenesis

Pipes¹,

Creemers²,

Olson³

2006

Genes Dev.

432

444

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The association of transcriptional coactivators with sequence-specific DNA-binding proteins provides versatility and specificity to gene regulation and expands the regulatory potential of individual cis-regulatory DNA sequences. Members of the myocardin family of coactivators activate genes involved in cell proliferation, migration, and myogenesis by associating with serum response factor (SRF). The partnership of myocardin family members and SRF also controls genes encoding components of the actin cytoskeleton and confers responsiveness to extracellular growth signals and intracellular changes in the cytoskeleton, thereby creating a transcriptional-cytoskeletal regulatory circuit. These functions are reflected in defects in smooth muscle differentiation and function in mice with mutations in myocardin family members. This article reviews the functions and mechanisms of action of the myocardin family of coactivators and the physiological significance of transcriptional coactivation in the context of signal-dependent and cell-type-specific gene regulation.The instructions for gene expression are "hard wired" into DNA sequence in the form of cis-regulatory elements that bind sequence-specific transcription factors and confer specialized patterns of gene expression (Howard and Davidson 2004). However, the binding of transcription factors to their cognate sites is often insufficient to account for the patterns of expression of their target genes. Indeed, it is not uncommon for a transcription factor to control genes with distinct or even mutually exclusive expression patterns. Many transcription factors are also relatively weak transcriptional activators and function by recruiting coactivators (or corepressors) that do not bind DNA directly but regulate transcription in a DNA sequence-specific manner by associating with DNA-bound factors (Spiegelman and Heinrich 2004). Thus, the association of DNA-binding proteins with accessory factors provides specificity and versatility to gene regulation and expands the regulatory potential of individual cis-regulatory elements.

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“…The t(1;22) translocation has only very rarely been associated with the AML-M7 cases that occur in association with trisomy 21; in general, AML-M7 with trisomy 21 is nearly always associated with mutations in the GATA1 gene (14,32). In t (1;22), the breakpoint on chromosome 1p13 is within a gene that has been variably named RBM15 for RNA-binding motif protein 15 and OTT (for one twenty-two translocation), and the breakpoint on chromosome 22 is within the MKL1 gene (also known as MAL or BSAC).…”

mentioning

confidence: 99%

“…The t(1;22) breakpoint on chromosome 1 is located within a 4-kb intron of the RBM15 gene downstream of the exon encoding the C-terminal SPOC domain, and it generates an inframe fusion with MKL1 that contains nearly the full-length coding regions of both RBM15 and MKL1 with the predicted chimeric protein containing 1,833 amino acids (1,15,34). Although the biological function of RBM15 is not yet known, SHARP, another member of the spen family of proteins that is conserved from Drosophila, is associated with transcriptional repression and can inhibit Notch signaling by binding to RBPJ (26,38).…”

mentioning

confidence: 99%

Rbm15 Modulates Notch-Induced Transcriptional Activation and Affects Myeloid Differentiation

Renda

Wang

et al. 2007

Molecular and Cellular Biology

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RBM15 is the fusion partner with MKL in the t(1;22) translocation of acute megakaryoblastic leukemia. To understand the role of the RBM15-MKL1 fusion protein in leukemia, we must understand the normal functions of RBM15 and MKL. Here, we show a role for Rbm15 in myelopoiesis. Rbm15 is expressed at highest levels in hematopoietic stem cells and at more moderate levels during myelopoiesis of murine cell lines and primary murine cells. Decreasing Rbm15 levels with RNA interference enhances differentiation of the 32DWT18 myeloid precursor cell line. Conversely, enforced expression of Rbm15 inhibits 32DWT18 differentiation. We show that Rbm15 alters Notch-induced HES1 promoter activity in a cell type-specific manner. Rbm15 inhibits Notch-induced HES1 transcription in nonhematopoietic cells but stimulates this activity in hematopoietic cell lines, including 32DWT18 and human erythroleukemia cells. Moreover, the N terminus of Rbm15 coimmunoprecipitates with RBPJ, a critical factor in Notch signaling, and the Rbm15 N terminus has a dominant negative effect, impairing activation of HES1 promoter activity by full-length-Rbm15. Thus, Rbm15 is differentially expressed during hematopoiesis and may act to inhibit myeloid differentiation in hematopoietic cells via a mechanism that is mediated by stimulation of Notch signaling via RBPJ.Acute megakaryoblastic leukemia (AML-M7, also referred to as AMKL) comprises approximately 10% of childhood AML, in which it frequently presents in infants with bone marrow fibrosis and progresses rapidly, with a median survival of 8 months. This phenotype is associated with the t(1;22)(p13; q13) translocation, which was first observed in several infants with AML-M7 (5) and subsequently confirmed by others to be associated almost exclusively with this type of AML (2, 30, 31, 34). The t(1;22) translocation has only very rarely been associated with the AML-M7 cases that occur in association with trisomy 21; in general, AML-M7 with trisomy 21 is nearly always associated with mutations in the GATA1 gene (14, 32). In t(1;22), the breakpoint on chromosome 1p13 is within a gene that has been variably named RBM15 for RNA-binding motif protein 15 and OTT (for one twenty-two translocation), and the breakpoint on chromosome 22 is within the MKL1 gene (also known as MAL or BSAC).The MKL1 gene product is a 4.5-kb transcript that is widely expressed in normal tissues (35) and encodes one of three members of the myocardin family. While these three members, i.e., MKL1, MKL2, and myocardin, are only 35% similar to one another at the protein level, they have several highly conserved domains, including RPEL repeats in the N terminus, a region with a B (basic amino acid) box and a glutamine-rich domain that is involved in binding to serum response factor, a leucine zipper-like domain that plays a role in homo-and heterodimerization, and a C-terminal transactivation domain. These proteins also have a SAP domain that, based on its homology to SAF-B, is predicted to associate with matrix attachment regions of transcrip...

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RBM15-MKL1 (OTT-MAL) fusion transcript in an adult acute myeloid leukemia patient

Cited by 17 publications

References 12 publications

C11orf95‐MKL2 is the resulting fusion oncogene of t(11;16)(q13;p13) in chondroid lipoma

C11orf95‐MKL2 is the resulting fusion oncogene of t(11;16)(q13;p13) in chondroid lipoma

The myocardin family of transcriptional coactivators: versatile regulators of cell growth, migration, and myogenesis

Rbm15 Modulates Notch-Induced Transcriptional Activation and Affects Myeloid Differentiation

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