Recurrent involvement of the MLL gene in adult T-lineage acute lymphoblastic leukemia

Hayette, Sandrine; Tigaud, Isabelle; Maguer-Satta, Véronique; Bartholin, Laurent; Thomas, Xavier; Charrin, C; Gadoux, Mylène; Magaud, Jean‐Pierre; Rimokh, Ruth

doi:10.1182/blood-2002-03-0717

Cited by 39 publications

(26 citation statements)

References 6 publications

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“…Recently, we have shown that the involvement of the MLL gene is also recurrent in T-cell ALL, with an incidence of more than 8% (2). This rearrangement is also found in patients with therapy-related leukemia induced by topoisomerase-inhibiting epipodophyllotoxins.…”

Section: Introductionmentioning

confidence: 95%

AF4p12, a Human Homologue to the furry Gene of Drosophila, as a Novel MLL Fusion Partner

Hayette

Cornillet‐Lefèbvre²,

Tigaud³

et al. 2005

Cancer Research

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More than 35 different partner genes with the mixed lineage leukemia (MLL) gene have been cloned from leukemia cells with translocations involving chromosome 11 band q23. In this study, we report on a novel fusion partner of the MLL gene, AF4p12, which we have identified as the human homologue to the furry gene of Drosophila. AF4p12, highly conserved in evolution, encodes a large protein of 3,105 amino acids. The expression of AF4p12 has been preferentially detected in colon, placenta, and brain tissues and in tumor cells of lymphoid origin. We show that the t(4;11)(p12;q23) translocation results in the creation of a chimeric RNA encoding a putative fusion protein containing 1,362 amino acids from the NH 2 -terminal part of MLL and 712 amino acids from the COOH-terminal part of AF4p12. FLT3 and HOXA9 genes are overexpressed in this leukemia. We found that the COOH-terminal part of AF4p12 fused to MLL contains a leucine zipper motif and exhibits transcriptional activation properties when fused to Gal4 DNA-binding domains in transient transfection assays. The AF4p12 fragment fused to MLL may contribute to the oncogenic activation of MLL, possibly through specific recruitment of the transcriptional machinery. (Cancer Res 2005; 65(15): 6521-5)

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Section: Introductionmentioning

confidence: 95%

AF4p12, a Human Homologue to the furry Gene of Drosophila, as a Novel MLL Fusion Partner

Hayette

Cornillet‐Lefèbvre²,

Tigaud³

et al. 2005

Cancer Research

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“…[1][2][3] Recent reports have shown that 11q23 translocations occur in up to 8% of T-ALLs, which were characterized by a poor clinical outcome. 4,5 Here, we present evidence of another high-risk group with frequent MLL gene translocations involving 82% (46 or 56) of the distinct CD19 ϩ /CD10 Ϫ /cyIgM ϩ pre-B ALL subset. …”

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confidence: 91%

CD10- pre-B acute lymphoblastic leukemia (ALL) is a distinct high-risk subgroup of adult ALL associated with a high frequency of MLL aberrations: results of the German Multicenter Trials for Adult ALL (GMALL)

Gleißner¹

2005

Blood

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, for the GMALL Study GroupImmunophenotyping disclosed CD10 negativity in 70 of 2408 cases of B-lineage acute lymphoblastic leukemia (ALL), although other criteria followed classification of pre-B ALL (eg, cytoplasmic immunoglobulin positivity). These blasts showed high myeloid antigen expression (60% CD65 positivity) and reacted with antibody 7.1 in 95% of the cases. MLL-AF4 fusion transcripts or an 11q23/MLL rearrangement or both were evident in 46 of 56 samples (82%). Although 83% of the patients achieved complete remission, the remission duration remained remarkably low: 141 days for MLL rearrangement-positive and 245 days for MLL rearrangement-negative CD10 ؊ pre-B ALL. Thus, the overall survival probability 3 years after diagnosis was 0. 34 IntroductionImmunologic subtyping and molecular genetic analysis allow riskadapted treatment of acute lymphoblastic leukemia (ALL). One poorprognosis subgroup of adult B-lineage precursor ALL is characterized by translocations involving the mixed lineage leukemia (MLL) gene on chromosome 11q23. These translocations occur in approximately 3% to 6% of all adult ALL and correlate with a younger age, a higher leukocyte count, and a CD19 ϩ /CD10 Ϫ /cytoplasmic(cy)IgM Ϫ immunophenotype (pro-B ALL) coexpressing myeloid marker. [1][2][3] Recent reports have shown that 11q23 translocations occur in up to 8% of T-ALLs, which were characterized by a poor clinical outcome. 4,5 Here, we present evidence of another high-risk group with frequent MLL gene translocations involving 82% (46 or 56) of the distinct CD19 ϩ /CD10 Ϫ /cyIgM ϩ pre-B ALL subset. Study designDual-staining immunophenotyping of 3168 newly diagnosed ALL specimens was performed with commercially available fluorochrome monoclonal antibody conjugates (Dako, Hamburg, Germany; BD Biosciences, San Jose, CA; BeckmanCoulter, Fullerton, CA) identifying pro-B ALL, TdT ϩ /CD19 ϩ /CD10 Ϫ /cyIgM Ϫ / surface(S)Ig Ϫ ; c-ALL, TdT ϩ /CD19 ϩ /CD10 ϩ /cyIgM Ϫ /SIg Ϫ ; and pre-B ALL, TdT ϩ /CD19 ϩ /CD10 ϩ /cyIgM ϩ /SIg Ϫ . 1,6,7 Ambiguous cases of CD10 ϩ B-lineage marker-positive blasts (5%-15% CD10 positivity) were rechecked by a second antibody (BD Biosciences, Dako). Only consistently negative samples (Ͻ 20% positive cells) were considered for CD10 negativity. Molecular detection of MLL-AF4 and BCR-ABL fusion as well as cytogenetic analysis were carried out as described elsewhere. [6][7][8][9][10][11] Fluorescence in situ hybridization (FISH) used directly labeled dual-color break-apart MLL rearrangement probes (Vysis, Downers Grove, IL). 7 At least 200 nuclei were scored, setting the cut-off value for false-positive nuclei at 10%. Patients were treated according the German Multicenter Adult ALL (GMALL) trials, 1,6,12 allocating MLL-AF4 ϩ patients to the high-risk arm. 13 The median follow-up was 25.6 months (range, 1.8-70.4 months) for survivors. The protocols were reviewed and approved by institutional review boards at each of the participating sites, and all patients provided informed consent prior to enrollment. Results and di...

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“…5 Most of the genomic breakpoints occur in a clustered region between exons 5 and 11 in an 8 kb genomic region, but some rearrangements have been recently observed outside this region in adult T-ALL. 6 More than 30 different partners resulting in various MLL FG transcripts have been identified (Table 1). 4,7 These rearrangements account for 5-10% of acquired chromosomal rearrangements in pediatric and adult ALL (B-and T-ALL), acute myeloblastic leukemia (AML), and poorly differentiated or bi-phenotypic leukemia and myelodysplastic syndromes (MDS).…”

Section: Introductionmentioning

confidence: 99%

“…4,7 These rearrangements account for 5-10% of acquired chromosomal rearrangements in pediatric and adult ALL (B-and T-ALL), acute myeloblastic leukemia (AML), and poorly differentiated or bi-phenotypic leukemia and myelodysplastic syndromes (MDS). 2,6 Strikingly, up to 80% of acute leukemia in neonates and infants, as well as a majority of secondary or treatmentrelated (ie topoisomerase II inhibitor induced) leukemia, involve a reciprocal clonal rearrangement of 11q23. [8][9][10] Analyses of leukemia karyotypes by several groups have revealed a relative association between particular translocations and subtypes of leukemia.…”

Section: Introductionmentioning

confidence: 99%

A diagnostic biochip for the comprehensive analysis of MLL translocations in acute leukemia

Maroc¹,

Morel²,

Beillard

et al. 2004

Leukemia

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Recurrent involvement of the MLL gene in adult T-lineage acute lymphoblastic leukemia

Cited by 39 publications

References 6 publications

AF4p12, a Human Homologue to the furry Gene of Drosophila, as a Novel MLL Fusion Partner

AF4p12, a Human Homologue to the furry Gene of Drosophila, as a Novel MLL Fusion Partner

CD10- pre-B acute lymphoblastic leukemia (ALL) is a distinct high-risk subgroup of adult ALL associated with a high frequency of MLL aberrations: results of the German Multicenter Trials for Adult ALL (GMALL)

A diagnostic biochip for the comprehensive analysis of MLL translocations in acute leukemia

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