DNA rearrangements and altered transcripts of the MLL gene in a human T‐all cell line karpas 45 with a t(X;II) (q13;q23) translocation

McCabe, Norah R.; Kipiniak, Magdalena; Kobayashi, Hirofumi; Thirman, Michael J.; Gill, Heidi; Rowley, Janet D.; Dı́az, Manuel O.

doi:10.1002/gcc.2870090311

Cited by 13 publications

(10 citation statements)

References 17 publications

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“…Participation of forkhead proteins in these cellular processes suggests their critical roles as tumor suppressors, which may be attenuated after chromosomal translocations in leukemias (7,27,40), as well as solid tumors (3,12,20). Forkhead proteins bind their cognate DNA sites through a conserved forkhead domain and appear to regulate target gene transcription through recruitment of coactivators such as CBP, p300, or SRC-1, with which they physically interact (43).…”

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“…Two MLL fusion partners, AFX (7,40) and FKHRL1 (27), and the related FKHR, comprise a subclass of forkhead/ winged helix transcription factors (1) that normally regulate genes involved in apoptosis and cell cycle progression (8,41). Participation of forkhead proteins in these cellular processes suggests their critical roles as tumor suppressors, which may be attenuated after chromosomal translocations in leukemias (7,27,40), as well as solid tumors (3,12,20).…”

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MLL-AFX Requires the Transcriptional Effector Domains of AFX To Transform Myeloid Progenitors and Transdominantly Interfere with Forkhead Protein Function

Cleary

2002

Molecular and Cellular Biology

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MLL-AFX is a fusion gene created by t(X;11) chromosomal translocations in a subset of acute leukemias of either myeloid or lymphoid derivation. It codes for a chimeric protein consisting of MLL fused to AFX, a forkhead transcription factor that normally regulates genes involved in apoptosis and cell cycle progression. We demonstrate here that forced expression of MLL-AFX enhances the self-renewal of hematopoietic progenitors in vitro and induces acute myeloid leukemias after long latencies in syngeneic recipient mice. MLL-AFX interacts with the transcriptional coactivator CBP, which is also a fusion partner for MLL in human leukemias. A potent minimal transactivation domain (CR3) at the C terminus of AFX mediates interactions with the KIX domain of CBP and is necessary for transformation of myeloid progenitors by MLL-AFX. However, CR3 alone is not sufficient, suggesting that simple acquisition of a transactivation domain per se does not activate the oncogenic potential of MLL. Rather, two conserved transcriptional effector domains (CR2 and CR3) of AFX are required for full oncogenicity of MLL-AFX and also endow it with the potential to competitively interfere with transcription and apoptosis mediated by wild-type forkhead proteins. Furthermore, a dominant-negative mutant of AFX containing CR2 and CR3 enhances the growth of myeloid progenitors in vitro, although considerably less effectively than does MLL-AFX. Taken together, these data suggest that recruitment of transcriptional cofactors utilized by forkhead proteins is a critical requirement for oncogenic action of MLL-AFX, which may impact both MLL-and forkhead-dependent transcriptional pathways.Rearrangements of the mixed lineage leukemia (MLL) gene (also known as HRX, ALL-1, and Htrx) result from chromosomal translocations in a subset of acute leukemias with lymphoid, myeloid, or biphenotypic features (16,25,56). MLL codes for a 431-kDa protein that is a structural and functional homolog of Drosophila trithorax, a positive regulator of Hox genes during embryonic development (24,26,48,61,62). Remarkably, MLL undergoes fusion with more than 30 different partner proteins as a result of chromosomal translocations, to yield chimeric proteins containing amino-terminal portions of MLL fused in-frame to a carboxy-terminal partner. MLL fusion partners are highly diverse but appear to comprise two general categories of proteins, either nuclear factors with putative roles in transcriptional regulation or cytoplasmic proteins that may be involved in signal transduction (14). The wide array and diverse functions of MLL fusion partners have suggested several possible mechanisms for the oncogenic activation of MLL, including positive and negative gain-of-function, as well as forced oligomerization (17,21).Knockin mouse models (11) and retroviral transduction or transplantation assays (36) support a gain-of-function mechanism for a subset of MLL fusion proteins in leukemogenesis. For several nuclear partners, this appears to be the consequence of transcriptional effector d...

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MLL-AFX Requires the Transcriptional Effector Domains of AFX To Transform Myeloid Progenitors and Transdominantly Interfere with Forkhead Protein Function

Cleary

2002

Molecular and Cellular Biology

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“…In fact, at least 20 different reciprocal translocations involving band 11q23 have been described. Some of the ALL-1 partner genes have been cloned and characterized: AFlp from chromosome 1; AF4 from chromosome 4; AF6 from chromosome 6; AF9 from chromosome 9; AFJ7 from chromosome 17; ENL from chromosome 19; and AFX from human chromosome X (5)(6)(7)(8)(9)(10)(11)(12). Among these different genes, only AF9 and ENL share sequence homology (8,9).…”

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Involvement of the ALL-1 gene in a solid tumor.

Baffa

Negrini

Schichman

et al. 1995

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

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Translocations involving chromosome band 11q23, found in 5-10% of human acute leukemias, disrupt the ALL-1 gene. This gene is fused by reciprocal translocation with a variety of other genes in acute lymphoblastic and myelogenous leukemias, and it undergoes self-fusion in acute myeloid leukemias with normal karyotype or trisomy 11. Here we report an alteration of the ALL-1 gene in a gastric carcinoma cell line (Mgc80-3). Characterization of this rearrangement revealed a three-way complex translocation, involving chromosomes 1 and 11, resulting in a partial duplication of the ALL-1 gene. Sequencing of reverse transcription-PCR products and Northern blot analysis showed that only the partially duplicated ALL-1 gene was transcribed, producing an mRNA with exon 8 fused to exon 2. This report of ALL-1 gene rearrangement in a solid tumor suggests that ALL-1 plays a role in the pathogenesis of some solid malignancies. The absence of the normal transcript in this cell line, in association with the loss-of-heterozygosity studies on chromosome 11q23 seen in solid tumors, suggests that ALL-1 is involved in tumorigenesis by a loss-of-function mechanism.

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“…In contrast to frequent involvement in B-lineage ALL and AML, MLL gene rearrangements have been reported rarely in T-cell ALL (McCabe et al, 1994). In this report, we characterize a case of T-cell ALL with an MLL gene rearrangement, which was apparently due to a cytogenetically undetected translocation and associated deletion involving the MLL gene and ENL (also known as MLLTI or LTGI9), a gene on 1 9~1 3 .…”

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Complex MLL rearrangement in a patient with T‐cell acute lymphoblastic leukemia

Chervinsky

Sait

Nowak

et al. 1995

Genes Chromosomes & Cancer

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MLL (also known as ALL-I, HTRX, or HRX) gene translocations are among the most common chromosomal abnormalities recognized in both B-lineage acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). However, MLL gene rearrangements are uncommon in T-cell ALL. We recently detected an MLL gene rearrangement in a patient with typical T-cell ALL. We recently detected an MLL gene rearrangement in a patient with typical T-cell ALL (CD2+, CD4+, CD5+, CD7+, CD8+, HLA DR-) and an apparently normal karyotype (46,XX). The rearrangement was cloned and characterized; a DNA fragment distal to the breakpoint was mapped by fluorescence in situ hybridization (FISH) to 19p13, indicating that the leukemic blasts had undergone a cytogenetically undetected rearrangement involving chromosomes 11 and 19. A reverse transcriptase-polymerase chain reaction (RT-PCR) assay demonstrated an in-frame fusion mRNA between the amino terminus of MLL and the carboxy terminus of ENL (also known as MLLT1 or LTG19), a gene that has been mapped to 19p13. In addition, MLL sequences distal (telomeric) to the breakpoint were deleted from the genome, which precludes the formation of a reciprocal ENL/MLL fusion protein. These findings suggest that an MLL/ENL fusion protein (and not a reciprocal ENL/MLL fusion) was likely to be pathogenic in this patient, and they reinforce previous studies showing that leukemic blasts with apparently normal karyotype may harbor MLL rearrangements. Additionally, this report provides the first conclusive evidence of an MLL/ENL gene fusion characterized at a molecular level in a patient with T-cell ALL.

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DNA rearrangements and altered transcripts of the MLL gene in a human T‐all cell line karpas 45 with a t(X;II) (q13;q23) translocation

Cited by 13 publications

References 17 publications

MLL-AFX Requires the Transcriptional Effector Domains of AFX To Transform Myeloid Progenitors and Transdominantly Interfere with Forkhead Protein Function

MLL-AFX Requires the Transcriptional Effector Domains of AFX To Transform Myeloid Progenitors and Transdominantly Interfere with Forkhead Protein Function

Involvement of the ALL-1 gene in a solid tumor.

Complex MLL rearrangement in a patient with T‐cell acute lymphoblastic leukemia

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