Biased distribution of chromosomal breakpoints involving the MLL gene in infants versus children and adults with t(4;11) ALL

Reichel, Martin; Gillert, Esther; Angermüller, Sieglinde; Hensel, Jan Patrick; Heidel, Florian H.; Lode, Martin; Leis, Thomas; Biondi, Andrea; Haas, Oskar A.; Strehl, Sabine; Panzer-Grümayer, E. Renate; Griesinger, Frank; Beck, J. D.; Greil, Johann; Fey, Georg H.; Uckun, Fatih M.; Marschalek, Rolf

doi:10.1038/sj.onc.1204401

Cited by 83 publications

(98 citation statements)

References 23 publications

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“…This interpretation solves the controversial situation found for 20% of t(4;11) leukemia patients, where only the presence of the MLL . AF4 fusion allele was successfully verified Janssen et al, 1994;Reichel et al, 2001). In both genetic situations selfrenewal would be granted, either by a Nanog-dependent 'stem cell program' or by HoxA genes in conjunction with Meis1.…”

Section: Discussionmentioning

confidence: 84%

Combined effects of the two reciprocal t(4;11) fusion proteins MLL·AF4 and AF4·MLL confer resistance to apoptosis, cell cycling capacity and growth transformation

et al. 2006

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The reciprocal chromosomal translocation t(4;11) is correlated with infant, childhood, adult and therapyrelated high-risk acute leukemia. Here, we investigated the biological effects of MLL . AF4, AF4 . MLL or the combination of both reciprocal fusion proteins in a conditional in vitro cell culture model system. Several parameters like cell growth, cell cycling capacity, apoptotic behavior and growth transformation were investigated under physiological and stress conditions. Co-transfected cells displayed the highest resistance against apoptotic triggers, cell cycling capacity and lossof-contact inhibition. These analyses were complemented by gene expression profiling experiments and specific gene signatures were established for each of the three cell lines. Interestingly, co-transfected cells strongly upregulate the homeobox gene Nanog. In combination with Oct4, the Nanog homeoprotein is steering maintenance of pluripotency and self-renewal in embryonic stem cells. Transcription of Nanog and other stem cell factors, like Oct4 and Bmi1, was verified in biopsy material of t(4;11) patient cells which express both reciprocal t(4;11) fusion genes. In conclusion, the presence of both reciprocal MLL fusion proteins confers biological properties known from t(4;11) leukemia, suggesting that each of the two fusion proteins contribute specific properties and, in combination, also synergistic effects to the leukemic phenotype.

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Section: Discussionmentioning

confidence: 84%

Combined effects of the two reciprocal t(4;11) fusion proteins MLL·AF4 and AF4·MLL confer resistance to apoptosis, cell cycling capacity and growth transformation

et al. 2006

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“…This complexity of the breakpoints is shared by MLL-AF4, TEL-AML1, PML-RARA, and CBFB-MYH11, translocations which occur in pediatric ALL as well as AML. [14][15][16]22,[55][56][57] These translocations like AML-ETO in children are not associated with etiologic causal agents in the vast…”

Section: Discussionmentioning

confidence: 99%

Molecular characterization of genomic AML1-ETO fusions in childhood leukemia

et al. 2001

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T(8;21) AML1(CBFA2)-ETO(MTG8)is the most common chromosomal translocation in acute myeloid leukemia (AML) in both children and adults. We sought to understand the structure and gain insight into the fusion process between AML1 and ETO by sequencing genomic fusions in 17 primary childhood AMLs and two cell lines with t(8;21). Reciprocal translocations were sequenced for seven of the 19 samples. We assumed a null hypothesis that the translocation breakpoints would be evenly distributed along the intronic breakpoint cluster regions. Testing for multimodality via smoothed bootstrap statistical methods suggested, however, the presence of two separate cluster regions within both the AML1 and ETO breakpoint cluster regions. ETO breakpoints were predominantly located in intron 1B in a defined cluster 5Ј of exon 1A (scan statistic P value = 0.00001). All patients with available RNA expressed an AML1-ETO mRNA fusion between exon 5 of AML1 and exon 2 of ETO. Since the structural restraints for the fusion protein of AML1-ETO exclude exon 1A, we reason that ETO intron 1B harbors a structural feature with propensity for breakage and/or recombination. Chromosomal breakpoints displayed evidence of fusion by a non-homologous end joining process, with microhomologies and nontemplate nucleotides at some fusion junctions. Breakpoints in general displayed similar complexity of duplications, deletions, and insertions to other common pediatric leukemia translocations (TEL-AML1, MLL-AF4, PML-RARA, CBFB-MYH11) that we and others have analyzed. Leukemia (2001Leukemia ( ) 15, 1906Leukemia ( -1913

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“…Current procedures to identify MLL rearrangements include cytogenetic analysis, 3,4 fluorescence in situ hybridization (FISH) experiments (for example, MLL split-signal FISH), [5][6][7] specific reverse transcriptase (RT)-PCR 8 or genomic PCR methods. 9,10 This repertoire of technologies was recently extended by a long-distance inverse PCR (LDI-PCR) method that uses small amounts of genomic DNA to determine any type of MLL gene rearrangement on the molecular level. 11 This includes chromosomal translocations, complex chromosomal rearrangements, gene internal duplications, deletions or inversions on chromosome 11q and MLL gene insertions into other chromosomes, or vice versa, the insertion of chromatin material into the MLL gene.…”

Section: Introductionmentioning

confidence: 99%

New insights to the MLL recombinome of acute leukemias

et al. 2009

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Chromosomal rearrangements of the human MLL gene are associated with high-risk pediatric, adult and therapy-associated acute leukemias. These patients need to be identified, treated appropriately and minimal residual disease was monitored by quantitative PCR techniques. Genomic DNA was isolated from individual acute leukemia patients to identify and characterize chromosomal rearrangements involving the human MLL gene. A total of 760 MLL-rearranged biopsy samples obtained from 384 pediatric and 376 adult leukemia patients were characterized at the molecular level. The distribution of MLL breakpoints for clinical subtypes (acute lymphoblastic leukemia, acute myeloid leukemia, pediatric and adult) and fused translocation partner genes (TPGs) will be presented, including novel MLL fusion genes. Combined data of our study and recently published data revealed 104 different MLL rearrangements of which 64 TPGs are now characterized on the molecular level. Nine TPGs seem to be predominantly involved in genetic recombinations of MLL: AFF1/AF4, MLLT3/ AF9, MLLT1/ENL, MLLT10/AF10, MLLT4/AF6, ELL, EPS15/AF1P, MLLT6/AF17 and SEPT6, respectively. Moreover, we describe for the first time the genetic network of reciprocal MLL gene fusions deriving from complex rearrangements.

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Biased distribution of chromosomal breakpoints involving the MLL gene in infants versus children and adults with t(4;11) ALL

Cited by 83 publications

References 23 publications

Combined effects of the two reciprocal t(4;11) fusion proteins MLL·AF4 and AF4·MLL confer resistance to apoptosis, cell cycling capacity and growth transformation

Combined effects of the two reciprocal t(4;11) fusion proteins MLL·AF4 and AF4·MLL confer resistance to apoptosis, cell cycling capacity and growth transformation

Molecular characterization of genomic AML1-ETO fusions in childhood leukemia

New insights to the MLL recombinome of acute leukemias

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