Molecular cytogenetic analysis of 10;11 rearrangements in acute myeloid leukemia

Limbergen, Heidi Van; Poppe, Bruce; Janssens, Ann; Bock, R. De; Paepe, Anne De; Noens, L.; Speleman, Franki

doi:10.1038/sj.leu.2402397

Cited by 51 publications

(38 citation statements)

References 38 publications

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“…Therefore, no chimeric transcript could be expressed from the reciprocal allele. Similar observations for inverse insertions were made for other MLL translocations that involved partner genes transcribed in centromeric direction, e.g., MLLT10 involved in t(10;11)(p12;q23) translocations and SEPT6 involved in t(X;11)(q24;q23) translocations (26,27).…”

Section: Discussionsupporting

confidence: 74%

Diagnostic tool for the identification of MLL rearrangements including unknown partner genes

Meyer

Schneider

Reichel

et al. 2004

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

169

157

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Approximately 50 different chromosomal translocations of the human MLL gene are currently known and associated with high-risk acute leukemia. The large number of different MLL translocation partner genes makes a precise diagnosis a demanding task. After their cytogenetic identification, only the most common MLL translocations are investigated by RT-PCR analyses, whereas infrequent or unknown MLL translocations are excluded from further analyses. Therefore, we aimed at establishing a method that enables the detection of any MLL rearrangement by using genomic DNA isolated from patient biopsy material. This goal was achieved by establishing a universal longdistance inverse-PCR approach that allows the identification of any kind of MLL rearrangement if located within the breakpoint cluster region. This method was applied to biopsy material derived from 40 leukemia patients known to carry MLL abnormalities. Thirty-six patients carried known MLL fusions (34 with der(11) and 2 with reciprocal alleles), whereas 3 patients were found to carry novel MLL fusions to ACACA, SELB, and SMAP1, respectively. One patient carried a genomic fusion between MLL and TIRAP, resulting from an interstitial deletion. Because of this interstitial deletion, portions of the MLL and TIRAP genes were deleted, together with 123 genes located within the 13-Mbp interval between both chromosomal loci. Therefore, this previously undescribed diagnostic tool has been proven successful for analyzing any MLL rearrangement including previously unrecognized partner genes. Furthermore, the determined patientspecific fusion sequences are useful for minimal residual disease monitoring of MLL associated acute leukemias.acute leukemia ͉ MLL translocations ͉ translocation partner genes C hromosomal translocations involving the human MLL gene are recurrently associated with high-risk acute leukemias (1-4). MLL translocations correlate with specific disease subtypes (acute myeloid and acute lymphocytic leukemias), a specific gene expression profile (5, 6), and outcome (favorable or poor), depending on the particular MLL fusion (7). Approximately 50 different MLL translocation partner genes have been identified, suggesting that the human MLL gene is a hot spot for illegitimate recombination events. During illegitimate recombination events, one MLL allele is reciprocally fused with one of the many translocation partner genes. The latter encode nuclear or cytosolic proteins that share only a little sequence homology; however, the fused portion of partner protein sequences is necessary to confer oncogenic potential.The unambiguous identification of these MLL translocations is necessary to support rapid clinical decisions and specific therapy regimens. Current procedures to diagnose MLL rearrangements include cytogenetic analysis, FISH experiments (e.g., split-signal FISH) (8), and specific RT-PCR methods. However, results of RT-PCR analyses are influenced strongly by the quality of the investigated RNA samples. Furthermore, only the most frequent MLL fusions routine...

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Section: Discussionsupporting

confidence: 74%

Diagnostic tool for the identification of MLL rearrangements including unknown partner genes

Meyer

Schneider

Reichel

et al. 2004

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

169

157

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“…Given the opposite orientation of MSI2 and EVI1 and the lack of karyotypic evidence for complex rearrangements, this result was indeed anticipated. 20 Further study of a possible MSI2/EVI1 fusion transcript was complicated by limited availability of patient sample. MSI2 rearrangements have also been linked to CML and myeloproliferative disorder disease progression.…”

Section: Resultsmentioning

confidence: 99%

EVI1 overexpression in t(3;17) positive myeloid malignancies results from juxtaposition of EVI1 to the MSI2 locus at 17q22

Weer

Speleman²,

Cauwelier³

et al. 2008

Haematologica

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Chromosomal translocations involving the EVI1 locus are a recurrent finding in myeloid leukemia and are associated with poor prognosis. In this study, we performed a detailed molecular characterization of the recurrent translocation t(3;17)(q26;q22) in 13 hematologic malignancies. The EVI1 gene locus was rearranged in all 13 patients and was associated with EVI1 overexpression. In 9 out of 13 patients, the 17q breakpoints clustered in a 250 kb region on band 17q22 encompassing the MSI2 (musashi homologue 2) gene.Expression analyses failed to demonstrate ectopic MSI2 expression or the presence of an MSI2/EVI1 fusion gene. In conclusion, we show for the first time that the t(3;17) is indeed a recurrent chromosomal aberration in myeloid malignancies. In keeping with findings in other recurrent 3q26 rearrangements, overexpression of the EVI1 gene appears to be the major contributor to leukemogenesis in patients with a t(3;17).

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“…32 The ins(10;11) is an uncommon cytogenetic abnormality in AML, but may be more frequent in AML-M0. 35,36 Studies showing an association of AML-M0 with poor outcome have generally been performed in adult patients. [1][2][3][6][7][8]28 In the subsets of adults treated intensively, these studies report CR rates of 25% to 62%, 2,3,5,6,28 with median CR durations of 1 to 12 months 3,6,28 and median survivals of 2 to 10 months.…”

Section: Discussionmentioning

confidence: 99%

Minimally differentiated acute myeloid leukemia (FAB AML-M0) is associated with an adverse outcome in children: a report from the Children's Oncology Group, studies CCG-2891 and CCG-2961

Barbaric

Alonzo

Gerbing

et al. 2006

Blood

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To assess the impact of minimally differentiated acute myeloid leukemia (AML-M0) morphology in children, we analyzed 2 sequential Children's Cancer Group AML clinical trials. We compared presenting characteristics and outcomes of 82 CCG-2891 and CCG-2961 patients with de novo, non-Down syndrome (DS) AML-M0 with those of 1620 patients with non-M0 AML, and of 10 CCG-2891 patients with DSassociated AML-M0 with those of 179 with DS-associated non-M0 AML. Morphology and cytogenetics were centrally reviewed. The non-DS AML-M0 children had a lower white blood cell (WBC) count (P ‫؍‬ .001) than their non-M0 counterparts and a higher incidence of chromosome 5 deletions (P ‫؍‬ .002), nonconstitutional trisomy 21 (P ‫؍‬ .027), and hypodiploidy (P ‫؍‬ .002). Outcome analyses considering all children with non-DS AML demonstrated no significant differences between M0 and non-M0 patients. Analyses restricted to intensive-timing CCG-2891 and CCG-2961 demonstrated comparable complete response (CR) rates (79% and 78%) between non-DS M0 and non-M0 patients. Overall survival (OS) from diagnosis (38% ؎ 14% versus 51% ؎ 3%; P ‫؍‬ .160) was not significantly different between the 2 groups. OS from end of induction (45% ؎ 17% versus 63% ؎ 3%; P ‫؍‬ .038), event-free survival (EFS; 23% ؎ 11% versus 41% ؎ 3%; P ‫؍‬ .018), and disease-free survival (DFS; 31% ؎ 14% versus 52% ؎ 3%; P ‫؍‬ .009) were inferior in the M0 group. There was no significant outcome difference between DS-associated AML-M0 and non-M0 children. This study suggests that intensively treated non-DSassociated AML-M0 children have an inferior outcome compared with children with non-M0 AML. (Blood.

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Molecular cytogenetic analysis of 10;11 rearrangements in acute myeloid leukemia

Cited by 51 publications

References 38 publications

Diagnostic tool for the identification of MLL rearrangements including unknown partner genes

Diagnostic tool for the identification of MLL rearrangements including unknown partner genes

EVI1 overexpression in t(3;17) positive myeloid malignancies results from juxtaposition of EVI1 to the MSI2 locus at 17q22

Minimally differentiated acute myeloid leukemia (FAB AML-M0) is associated with an adverse outcome in children: a report from the Children's Oncology Group, studies CCG-2891 and CCG-2961

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