Fusion of two novel genes, RBM15 and MKL1, in the t(1;22)(p13;q13) of acute megakaryoblastic leukemia

Ma, Zhigui; Morris, Stephan W.; Valentine, Virginia; Li, Martin; Herbrick, Jo-Anne; Cui, Xiaoli; Bouman, Derek; Li, Yue; Mehta, Perdeep K.; Nižetić, Dean; Kaneko, Yasuhiko; Chan, Godfrey C. F.; Li, Chan; Squire, Jeremy A.; Scherer, Stephen W.; Hitzler, Johann

doi:10.1038/90054

Cited by 269 publications

(198 citation statements)

References 15 publications

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“…Although the cytogenetic report did not show a standard karyotype [t(1;22)(p13;q13)] or a complex karyotype (chromosome 1, 22, and other chromosome involved), recent studies suggest that the RBM15-MKL1 (OTT-MAL) fusion transcript which was located on the derivative chromosome 22 and not on the derivative chromosome 1 [7][8][9]. RT-PCR and sequence data support the presence of this abnormal fusion transcript in our patient.…”

Section: Discussionsupporting

confidence: 47%

“…Recently, two genes, RBM15 (RNA-binding motif protein-15, also known as OTT (''one twenty-two'')) on chromosome 1 and MKL1 (megakaryocytic leukemia-1, also known as MAL (megakaryocytic acute leukemia)) on chromosome 22, were found to be involved in the translocation [7][8][9]. Both genes possess related sequences in the Drosophila genome with the RBM15 (OTT) gene encoding three RNA-recognition motifs and a spen paralog and ortholog C-terminal domain and the MKL1 (MAL) gene encoding an SAP DNA-binding motif, which is involved in chromatin organization.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2005

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The t(1;22)(p13;q13) is a nonrandom chromosomal abnormality in acute leukemia with the fusion oncogene, RBM15-MKL1 (OTT-MAL), identified recently. However, this abnormality has been described only in infants and young children with acute megakaryoblastic leukemia (AMKL). We report a 59-year-old male patient with the diagnosis of acute myeloid leukemia, subtype M1, who harbors an abnormal chromosome +der(1)t(1;22)(p13;q13). The RBM15-MKL1 (OTT-MAL) fusion transcript was also confirmed by the reverse transcriptase-polymerase chain reaction. This unusual abnormality is rare in adult cases of leukemia, and in children it is restricted to AMKL. This report is accompanied by a review of the literature on the t(1;22)(p13;q13). Am.

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Section: Discussionsupporting

confidence: 47%

Section: Introductionmentioning

confidence: 99%

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

et al. 2005

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“…MKL1 participates in a fused gene product generated by a translocation event in acute megakaryoblastic leukemia. 40 The EP300 transcriptional coactivator protein is specifically inhibited by the adenovirus oncoprotein E1A and somatic mutations linked to EP300 alterations have been reported in a small proportion of colorectal, breast and pancreatic cancers. 41 The genes DJ1042K10, with a RUN domain that was found in Rap and Rab GTPases.…”

Section: Discussionmentioning

confidence: 99%

Frequent LOH on 22q12.3 and TIMP-3 inactivation occur in the progression to secondary glioblastomas

Nakamura

Ishida

Shimada

et al. 2005

Laboratory Investigation

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Frequent allelic losses on the long arm of chromosome 22 (22q) in gliomas indicate the presence of tumor suppressor gene (TSG) at this location. However, the target gene(s) residing in this chromosome are still unknown and their putative roles in the development of astrocytic tumors, especially in secondary glioblastoma, have not yet been defined. To compile a precise physical map for the region of common deletions in astrocytic tumors, we performed a high-density loss of heterozygosity (LOH) analysis using 31 polymorphic microsatellite markers spanning 22q in a series of grade II diffuse astrocytomas, anaplastic astrocytomas, primary glioblastomas, and secondary glioblastomas that had evolved from lower grade astrocytomas. LOH was found at one or more loci in 33% (12/36) of grade II diffuse astrocytomas, in 40% (4/10) of anaplastic astrocytomas, in 41% (26/64) of primary glioblastomas, and in 82% (23/28) of secondary glioblastomas. Characterization of the 22q deletions in primary glioblastomas identified two sites of minimally deleted regions at 22q12.3-13.2 and 22q13.31. Interestingly, 22 of 23 secondary glioblastomas affected shared a deletion in the same small (957 kb) region of 22q12.3, a region in which the human tissue inhibitor of metalloproteinases-3 (TIMP-3) is located. Investigation of the promoter methylation and expression of this gene indicated that frequent hypermethylation correlated with loss of TIMP-3 expression in secondary glioblastoma. This epigenetic change was significantly correlated to poor survival in eight patients with grade II diffuse astrocytoma. Our results suggest that a 957 kb locus, located at 22q12.3, may contain the putative TSG, TIMP-3, that appears to be relevant to progression to secondary glioblastoma and subsequently to the prognosis of grade II diffuse astrocytoma. In addition, the possibility of other putative TSGs on 22q12.3-13.2 and 22q13.31 that may also be involved in the development of primary glioblastomas cannot be ruled out.

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“…We recently identified megakaryoblastic leukemia-1 (MKL1), a protein with a similarity to myocardin, as a potent transcriptional activator of SRF that is broadly expressed in many tissues (31). MKL1/ MAL was originally identified as part of a fusion protein with RBM15/OTT at a t(1;22) translocation in acute megakaryoblastic leukemia (32,33). Others have also recently identified MKL1/MAL/BSAC/MRTF-A as an activator of SRF (34 -36).…”

mentioning

confidence: 99%

Megakaryoblastic Leukemia-1/2, a Transcriptional Co-activator of Serum Response Factor, Is Required for Skeletal Myogenic Differentiation

Selvaraj

Prywes

2003

Journal of Biological Chemistry

128

146

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Serum response factor (SRF) is required for the expression of a wide variety of muscle-specific genes that are expressed upon differentiation and is thus required for both striated and smooth muscle differentiation in addition to its role in regulating growth factor-inducible genes. A heart and smooth muscle-specific SRF co-activator, myocardin, has been shown to be required for cardiac development and smooth muscle differentiation. However, no such co-factors of SRF have been identified in the skeletal myogenic differentiation program. Myocardin and the related transcription factor megakaryoblastic leukemia-1 (MKL1/MAL/MRTF-A) can strongly potentiate the activity of SRF. Here we report the cloning of the third member of the myocardin/MKL family in humans, MKL2. MKL2 binds to and activates SRF similar to myocardin and MKL1. To determine the role of these factors in skeletal myogenic differentiation we used a dominant negative MKL2 to show that the MKL family of proteins is required for skeletal myogenic differentiation. Expression of the dominant negative protein in C2C12 skeletal myoblasts blocked the differentiation-induced expression of the SRF target genes skeletal ␣-actin and ␣-myosin heavy chain and blocked differentiation of the myoblasts to myotubes in vitro. C2C12 cells express both MKL1 and MKL2, but not myocardin, implicating MKL1 and/or MKL2 in the requirement for skeletal myogenic differentiation. MKL1 was predominantly cytoplasmic in C2C12 cells, with a small amount in the nucleus, however, no movement of MKL1 to the nucleus was observed upon differentiation.

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Fusion of two novel genes, RBM15 and MKL1, in the t(1;22)(p13;q13) of acute megakaryoblastic leukemia

Cited by 269 publications

References 15 publications

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

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

Frequent LOH on 22q12.3 and TIMP-3 inactivation occur in the progression to secondary glioblastomas

Megakaryoblastic Leukemia-1/2, a Transcriptional Co-activator of Serum Response Factor, Is Required for Skeletal Myogenic Differentiation

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