NovelMLL-CBP fusion transcript in therapy-related chronic myelomonocytic leukemia with a t(11;16) (q23;p13) chromosome translocation

Satake, Noriko; Ishida, Yasushi; Otoh, Yoshiko; Hinohara, Shin Ichi; Kobayashi, Hirofumi; Sakashita, Akihiko; Maseki, Nobuo; Kaneko, Yasuhiko

doi:10.1002/(sici)1098-2264(199709)20:1<60::aid-gcc9>3.0.co;2-7

Cited by 82 publications

(33 citation statements)

References 24 publications

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“…Conversely, MLL-EB1 and MLL-CBP, which are associated with lower Meis1 expression in our model, have only rarely been observed in human AML (a single case for MLL-EB1) (Fu et al 2005). Furthermore, MLL-CBP is associated with human MDS (Satake et al 1997) and induces an MDS-like disorder in mice (J. , which are premalignant conditions characterized by altered self-renewal and differentiation potentials, suggesting that MLL-CBP initiates transformation but does not readily facilitate progression to AML. Thus, MEIS family gene expression levels in subclinical initiated progenitors harboring MLL chromosomal translocations may influence the probability of acquiring necessary secondary mutations for their conversion into LSCs capable of inducing clinical leukemia.…”

Section: Genes and Development 2769mentioning

confidence: 65%

Meis1 is an essential and rate-limiting regulator of MLL leukemia stem cell potential

Wong¹,

Iwasaki²,

Somervaille³

et al. 2007

Genes Dev.

260

273

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Oncogenic mutations of the MLL histone methyltransferase confer an unusual ability to transform non-self-renewing myeloid progenitors into leukemia stem cells (LSCs) by mechanisms that remain poorly defined. Misregulation of Hox genes is likely to be critical for LSC induction and maintenance but alone it does not recapitulate the phenotype and biology of MLL leukemias, which are clinically heterogeneouspresumably reflecting differences in LSC biology and/or frequency. TALE (three-amino-acid loop extension) class homeodomain proteins of the Pbx and Meis families are also misexpressed in this context, and we thus employed knockout, knockdown, and dominant-negative genetic techniques to investigate the requirements and contributions of these factors in MLL oncoprotein-induced acute myeloid leukemia. Our studies show that induction and maintenance of MLL transformation requires Meis1 and is codependent on the redundant contributions of Pbx2 and Pbx3. Meis1 in particular serves a major role in establishing LSC potential, and determines LSC frequency by quantitatively regulating the extent of self-renewal, differentiation arrest, and cycling, as well as the rate of in vivo LSC generation from myeloid progenitors. Thus, TALE proteins are critical downstream effectors within an essential homeoprotein network that serves a rate-limiting regulatory role in MLL leukemogenesis.[Keywords: Leukemia stem cells; MLL; Meis1; Pbx; TALE homeodomain proteins] Supplemental material is available at http://www.genesdev.org.

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Section: Genes and Development 2769mentioning

confidence: 65%

Meis1 is an essential and rate-limiting regulator of MLL leukemia stem cell potential

Wong¹,

Iwasaki²,

Somervaille³

et al. 2007

Genes Dev.

260

273

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“…8 MLL-CBP fusion transcripts have also been detected. 7,9,10 Analyses of the CBP breakpoints in MLL-CBP and CBP-MLL fusion transcripts in two t (11;16) patients revealed that three of the CBP breakpoints exactly correspond to the site of the previously reported t(8;16) breakpoint, while one additional breakpoint was localized further downstream, yet still within the 5′ half of CBP gene. 9 Germline mutations inactivating one CBP allele cause the Rubinstein-Taybi syndrome (RTS).…”

Section: Introductionmentioning

confidence: 80%

“…4,5 Two different somatic translocations involving the CBP gene are found in acute myelogenous leukemia (AML): the t(8;16)(p11;p13.3) and the t(11;16)(q23;p13.3). 4,[6][7][8][9][10] Moreover, constitutional translocations disrupting the CBP gene lead to the Rubinstein-Taybi syndrome (RTS), a complex developmental disorder that among other symptoms, leads to an increased incidence of neoplasia. 5 Of the two leukemia-associated translocations, the t(8;16) is the more common, with an occurrence of four per 1000 AML patients.…”

Section: Introductionmentioning

confidence: 99%

Detection of CBP rearrangements in acute myelogenous leukemia with t(8;16)

et al. 1997

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The CREB-binding protein (CBP) is a large nuclear protein that regulates many signal transduction pathways and is involved in chromatin-mediated transcription. The translocation t(8;16)(p11;p13.3) consistently disrupts two genes: the CBP gene on chromosome band 16p13.3 and the MOZ gene on chromosome band 8p11. Although a fusion of these two genes as a result of the translocation is expected, attempts at detecting the fusion transcript by reverse transcriptase polymerase chain reaction (RT-PCR) have proven difficult; to date, only one inframe CBP/MOZ fusion transcript has been reported. We therefore sought other reliable means of detecting CBP rearrangements. We applied fluorescence in situ hybridization (FISH) and Southern blot analyses to a series of AML patients with a t(8;16) and detected DNA rearrangements of both the CBP and the MOZ loci in all cases tested. All six cases examined for CBP rearrangements have breakpoints within a 13 kb breakpoint cluster region at the 5′ end of the CBP gene. Additionally, we used a MOZ cDNA probe to construct a surrounding cosmid contig and detect DNA rearrangements in three t(8;16) cases, all of which display rearrangements within a 6 kb genomic fragment of the MOZ gene. We have thus developed a series of cosmid probes that consistently detect the disruption of the CBP gene in t(8;16) patients. These clones could potentially be used to screen other cancer-associated or congenital translocations involving chromosome band 16p13.3 as well.

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“…Certain genes which encode proteins with HAT activity or potential HAT activity, such as the monocytic leukemia zinc finger protein (MOZ), CREB-binding protein (CBP), p300 and TIF2, are targets of translocations found in AML, myelodysplastic syndrome (MDS) and acute mixed lineage leukemia. [9][10][11][12][13][14][15] The MOZ gene was shown to be fused to the CBP gene and the TIF2 gene in the translocation t(8;16) and inv (8), respectively. [9][10][11] We have found that p300 forms a fusion protein with MLL through the t(11;22) translocation in AML.…”

Section: Introductionmentioning

confidence: 99%

Fusion of MOZ and p300 histone acetyltransferases in acute monocytic leukemia with a t(8;22)(p11;q13) chromosome translocation

et al. 2001

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Histone acetyltransferase p300 functions as a transcriptional co-activator which interacts with a number of transcription factors. Monocytic leukemia zinc finger protein (MOZ) has histone acetyltransferase activity. We report the fusion of the MOZ gene to the p300 gene in acute myeloid leukemia with translocation t(8;22)(p11;q13). FISH and Southern blot analyses showed the rearrangement of the MOZ and p300 genes. We determined the genomic structure of the p300 and the MOZ genes and the breakpoints of the translocation. Analysis of fusion transcripts indicated that the zinc finger and acetyltransferase domains of MOZ are fused to a largely intact p300. These results suggest that MOZ-p300, which has two acetyltransferase domains, could be involved in leukemogenesis through aberrant regulation of histone acetylation. Leukemia (2001) 15, 89-94.

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NovelMLL-CBP fusion transcript in therapy-related chronic myelomonocytic leukemia with a t(11;16) (q23;p13) chromosome translocation

Cited by 82 publications

References 24 publications

Meis1 is an essential and rate-limiting regulator of MLL leukemia stem cell potential

Meis1 is an essential and rate-limiting regulator of MLL leukemia stem cell potential

Detection of CBP rearrangements in acute myelogenous leukemia with t(8;16)

Fusion of MOZ and p300 histone acetyltransferases in acute monocytic leukemia with a t(8;22)(p11;q13) chromosome translocation

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