A trithorax–like gene is interrupted by chromosome 11q23 translocations in acute leukaemias

Djabali, Malek; Selleri, Licia; Parry, Pauline; Bower, Mark; Young, Bryan D.; Evans, Glen A.

doi:10.1038/ng1092-113

Cited by 444 publications

(276 citation statements)

References 32 publications

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“…This locus shows homology to sequences within the Drosophila 'trithorax' gene, a developmental regulator. 7,8 As these aberrations were found in AML as well as acute lymphoblastic leukemia (ALL), the gene was called mixedlineage leukemia. 9 Recent studies show that the MLL group itself is genetically and clinically heterogeneous, as more than 60 different translocation partners of the MLL gene with differences in outcome have been described to date.…”

Section: Introductionmentioning

confidence: 99%

The heterogeneity of pediatric MLL-rearranged acute myeloid leukemia

et al. 2011

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Translocations involving the mixed-lineage leukemia (MLL) gene, localized at 11q23, comprise 15 to 20% of all pediatric acute myeloid leukemia (AML) cases. This review summarizes current knowledge about the etiology, biology, clinical characteristics and differences in outcome in MLL-rearranged pediatric AML. Furthermore, we discuss the role of cooperating events in MLL-rearranged pediatric AML, and future therapeutic strategies to improve outcome. We conclude that MLL-rearranged pediatric AML is a heterogeneous disease, and prognosis depends on various factors, for example, translocation partner, age, WBC and additional cytogenetic aberrations. The relationship of outcome with specific translocation partners requires that they be searched for in the diagnostic work-up of AML. To achieve further improvements in outcome, unraveling the biology of MLL-rearranged pediatric AML is warranted.

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Section: Introductionmentioning

confidence: 99%

The heterogeneity of pediatric MLL-rearranged acute myeloid leukemia

et al. 2011

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“…[4][5][6][7][8] Since the first descriptions of t(4;11) in acute lymphoblastic leukemia (ALL) in the latter half of the 1970s, 9-11 more than 350 cases with this translocation have been reported. 5 Recent molecular genetic investigations have revealed that abnormalities involving 11q23 often lead to rearrangement of the MLL (ALL1, HRX, HTRX1) gene [12][13][14][15][16] and that the t(4;11) results in a fusion between the MLL and the AF4 (FEL, LTG4, MLLT2) genes. [17][18][19][20][21] The identification of this chimeric transcript, which occasionally is also detected in leukemias lacking the t(4;11) cytogenetically, has provided the necessary information to establish reverse-transcriptase polymerase chain reaction assays for rapid and sensitive detection of the abnormality and for disease monitoring.…”

Section: Introductionmentioning

confidence: 99%

Hematologic malignancies with t(4;11)(q21;q23) – a cytogenetic, morphologic, immunophenotypic and clinical study of 183 cases

et al. 1998

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A total of 183 hematologic malignancies with t(4;11)(q21;q23), including five variant translocations, were collected by the Workshop. Clinical, morphologic and immunophenotypic features were compiled, and karyotypes with variant t(4;11) or secondary chromosomal aberrations were reviewed. All cases were acute leukemias (AL): 173 acute lymphoblastic leukemias (ALL), six acute myeloid leukemias (AML), three unclassifiable AL, and one biphenotypic AL. Ten patients had treatment-associated AL. Females were overrepresented (104 vs 79) and the age distribution was clearly nonrandom; 34% of the cases occurred in infants below the age of 12 months. The remaining AL were evenly distributed among the other age groups, with the oldest patient being 79 years old. An increased white blood cell count (WBC) was reported in more than 90% of the cases, with hyperleukocytosis (у100 × 10 9 /l) in 64%. Additional chromosomal changes were detected in 55 (30%) cases, most often gain of the X chromosome, i(7)(q10), and trisomy 8, with frequent breakpoints in 1p36, 1q21, 7q10, 11p15, 12p13, 17p11, and 17p10. All recurrent secondary changes resulted in genomic imbalances, in particular gains of 1q, 7q, 8, and X and losses of 7p and 17p. Event-free and overall survival (EFS and OS) could be ascertained in 170 and 171 patients, respectively. Kaplan-Meier estimates of EFS and OS showed no differences with regard to gender, WBC, or presence of secondary chromosomal abnormalities, and there was no increase of EFS or OS among the 55 cases that had undergone bone marrow transplantation. However, age had an important prognostic impact, with significantly (P Ͻ 0.0001) longer EFS and OS in children 2-9 years old than among infants and younger children, patients aged between 10 and 39 years and older adults.

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“…The analysis of chromosomal translocations a ecting chromosome 11 at band q23 in leukaemias has shown that these events involve fusions between the human trithorax (MLL) gene (Djabali et al, 1992;Gu et al, 1992;Tkachuk et al, 1992;Ziemin-van der Poel et al, 1991) and a variety of partner genes each providing a COOH region to the resultant fusion protein. These translocations result in in-frame fusions suggesting an important role for the di erent COOH regions in the oncogenic transformation.…”

Section: Introductionmentioning

confidence: 99%

The cloning, mapping and expression of a novel gene, BRL, related to the AF10 leukaemia gene

McCullagh¹,

Chaplin²,

Meerabux³

et al. 1999

Oncogene

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The MLL gene is reciprocally translocated with one of a number of di erent partner genes in a proportion of human acute leukaemias. The precise mechanism of oncogenic transformation is unclear since most of the partner genes encode unrelated proteins. However, two partner genes, AF10 and AF17 are related through the presence of a cysteine rich region and a leucine zipper. The identi®cation of other proteins with these structures will aid our understanding of their role in normal and leukaemic cells. We report the cloning of a novel human gene (BRL) which encodes a protein containing a cysteine rich region related to that of AF10 and AF17 and is overall most closely related to the previously known protein BR140. BRL maps to chromosome 22q13 and shows high levels of expression in testis and several cell lines. The deduced protein sequence also contains a bromodomain, four potential LXXLL motifs and four predicted nuclear localization signals. A monoclonal antibody raised to a BRL peptide sequence con®rmed its widespread expression as a 120 Kd protein and demonstrated localization to the nucleus within spermatocytes.

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A trithorax–like gene is interrupted by chromosome 11q23 translocations in acute leukaemias

Cited by 444 publications

References 32 publications

The heterogeneity of pediatric MLL-rearranged acute myeloid leukemia

The heterogeneity of pediatric MLL-rearranged acute myeloid leukemia

Hematologic malignancies with t(4;11)(q21;q23) – a cytogenetic, morphologic, immunophenotypic and clinical study of 183 cases

The cloning, mapping and expression of a novel gene, BRL, related to the AF10 leukaemia gene

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