11q23 Aberration and MLL Gene Status in Acute Leukemia
11q23 Aberration and MLL Gene Status in Acute Leukemia
Structural abnormality of the 11q23 band (11q23+) bearing the MLL gene translocation (MLL+) is a recurrent chromosome change observed in 3% to 7% of acute lymphoblastic leukemias and in 3% to 4% of acute myeloblastic leukemias. The resolution of conventional cytogenetics (CC) in detecting 11q23 rearrangement is limited when the translocative partner has a telomeric location; furthermore, CC can barely discriminate between true 11q23+/MLL+ and rearrangements clustering within the 11q22~25 region without MLL involvement (MLL-). We characterized a series of 378 consecutive patients with adult acute leukemia by using CC, fluorescence in situ hybridization (FISH), and multiplex karyotyping (M-FISH) analysis. Our aim was to define the frequency of cryptic MLL+ cases and the frequency of MLL+ within 11q22~25+ cases. As expected, FISH was more sensitive than CC in detecting MLL+ cases, but rather unexpectedly, 9 (45%) of 20 patients with 11q22~25+ were MLL-. A better characterization of 11q22~25+/MLL- leukemias is relevant for the identification of new, recurrent translocations. Moreover, these cases should be readily distinguishable from 11q23+/MLL+ cases. We recommend that karyotypic analysis always be complemented by molecular or FISH methods to unravel MLL rearrangements.
Structural abnormality of the 11q23 band (11q23+) bearing the MLL gene translocation (MLL+) is a recurrent chromosome change in leukemia described in acute myeloblastic leukemia (AML) and in acute lymphoblastic leukemia (ALL), with a peak incidence in infant leukemia. A proposal by the World Health Organization specifies a separate category for AML with 11q23+/MLL+. This notion has been supported recently by biologic studies: microarray analyses have shown that MLL+ acute leukemias (ALs) have a peculiar gene-profiling pattern that distinguishes them from all other ALs and that MLL+ leukemic blasts resemble very immature progenitor cells. Furthermore, these studies showed that MLL+ leukemias are a separate entity when compared with AML with MLL partial tandem duplication (MLL-PTD), a recently identified genetic aberration observed in a sizable proportion of AMLs.
Extensive cytogenetic and molecular studies have shown that 11q23/MLL is a highly promiscuous locus: more than 50 chromosomal loci have been described as 11q23 chromosome partners, whereas more than 30 MLL partner genes have been characterized. It also should be mentioned that t(11q23) might involve genes other than MLL and that conventional cytogenetics can barely discriminate between true 11q23+/MLL+ and rearrangements clustering within the 11q22~25 region without MLL involvement.
Because t(9;11)(p21;q23) bearing the MLL/AF9 gene fusion in AML and t(4;11) with MLL/AF4 gene fusion in infant leukemia are the most common types, these translocations often are referred to as classic translocation, whereas all other variants are reported as v11q23.
11q23+/MLL+ is described in 3% to 4% of AML cases and is more frequent in younger subjects with de novo (5%-7%) AML or with t-AML (10%-15%) evolving after chemotherapy. In older patients with AML (60 years or older), it is observed rarely. The majority of 11q23+/MLL+ AML cases have monocytoid differentiation features and are classified in the M4 and M5 leukemia French-American-British (FAB) subtypes. In adult ALL, the overall incidence of 11q23+/MLL+ is reported to be around 3% to 7%, but in pro-B-cell ALL, it accounts for more than 30% of chromosomal aberrations.
While t(4;11) ALL has an established dismal prognosis, the clinical outcome of 11q23+/MLL+ AML is more heterogeneous. The Medical Research Council and the Southwest Oncology Group classify the risk for patients with AML with t(9;11) as intermediate and poor, respectively. Even more disagreement surrounds the prognostic relevance of classic t(9;11) vs v11q23: some clinical trials reported that patients with t(9;11) fared better than patients with v11q23, whereas other studies failed to identify differences. These discrepancies probably reflect the marked biologic heterogeneity of 11q23 aberrations. Furthermore, because many v11q23 translocations are rare translocations, the clinical impact of specific single variants is difficult to extrapolate, even from large studies on 11q23 AL.
Recently, the combined use of conventional cytogenetics, reverse transcriptase-polymerase chain reaction (RT-PCR), Southern blot analysis, and fluorescence in situ hybridization (FISH) in limited AL series has revealed that discrepant results with MLL involvement might become evident, and a high incidence of patients with cryptic MLL+ leukemia were observed in 2 pediatric series. Because the majority of clinical trials include only karyotype data, it is reasonable to speculate that beyond biologic heterogeneity, these discrepancies also are due partly to the low accuracy of conventional cytogenetics.
We describe our findings in a series of 378 consecutive cases of adult AL, studied with conventional cytogenetics, FISH, and multiplex karyotyping (M-FISH) analysis. The aim of the study was to define the incidence of cryptic MLL gene translocation and the incidence of MLL gene rearrangement within 11q22~25+ cases.
Structural abnormality of the 11q23 band (11q23+) bearing the MLL gene translocation (MLL+) is a recurrent chromosome change observed in 3% to 7% of acute lymphoblastic leukemias and in 3% to 4% of acute myeloblastic leukemias. The resolution of conventional cytogenetics (CC) in detecting 11q23 rearrangement is limited when the translocative partner has a telomeric location; furthermore, CC can barely discriminate between true 11q23+/MLL+ and rearrangements clustering within the 11q22~25 region without MLL involvement (MLL-). We characterized a series of 378 consecutive patients with adult acute leukemia by using CC, fluorescence in situ hybridization (FISH), and multiplex karyotyping (M-FISH) analysis. Our aim was to define the frequency of cryptic MLL+ cases and the frequency of MLL+ within 11q22~25+ cases. As expected, FISH was more sensitive than CC in detecting MLL+ cases, but rather unexpectedly, 9 (45%) of 20 patients with 11q22~25+ were MLL-. A better characterization of 11q22~25+/MLL- leukemias is relevant for the identification of new, recurrent translocations. Moreover, these cases should be readily distinguishable from 11q23+/MLL+ cases. We recommend that karyotypic analysis always be complemented by molecular or FISH methods to unravel MLL rearrangements.
Structural abnormality of the 11q23 band (11q23+) bearing the MLL gene translocation (MLL+) is a recurrent chromosome change in leukemia described in acute myeloblastic leukemia (AML) and in acute lymphoblastic leukemia (ALL), with a peak incidence in infant leukemia. A proposal by the World Health Organization specifies a separate category for AML with 11q23+/MLL+. This notion has been supported recently by biologic studies: microarray analyses have shown that MLL+ acute leukemias (ALs) have a peculiar gene-profiling pattern that distinguishes them from all other ALs and that MLL+ leukemic blasts resemble very immature progenitor cells. Furthermore, these studies showed that MLL+ leukemias are a separate entity when compared with AML with MLL partial tandem duplication (MLL-PTD), a recently identified genetic aberration observed in a sizable proportion of AMLs.
Extensive cytogenetic and molecular studies have shown that 11q23/MLL is a highly promiscuous locus: more than 50 chromosomal loci have been described as 11q23 chromosome partners, whereas more than 30 MLL partner genes have been characterized. It also should be mentioned that t(11q23) might involve genes other than MLL and that conventional cytogenetics can barely discriminate between true 11q23+/MLL+ and rearrangements clustering within the 11q22~25 region without MLL involvement.
Because t(9;11)(p21;q23) bearing the MLL/AF9 gene fusion in AML and t(4;11) with MLL/AF4 gene fusion in infant leukemia are the most common types, these translocations often are referred to as classic translocation, whereas all other variants are reported as v11q23.
11q23+/MLL+ is described in 3% to 4% of AML cases and is more frequent in younger subjects with de novo (5%-7%) AML or with t-AML (10%-15%) evolving after chemotherapy. In older patients with AML (60 years or older), it is observed rarely. The majority of 11q23+/MLL+ AML cases have monocytoid differentiation features and are classified in the M4 and M5 leukemia French-American-British (FAB) subtypes. In adult ALL, the overall incidence of 11q23+/MLL+ is reported to be around 3% to 7%, but in pro-B-cell ALL, it accounts for more than 30% of chromosomal aberrations.
While t(4;11) ALL has an established dismal prognosis, the clinical outcome of 11q23+/MLL+ AML is more heterogeneous. The Medical Research Council and the Southwest Oncology Group classify the risk for patients with AML with t(9;11) as intermediate and poor, respectively. Even more disagreement surrounds the prognostic relevance of classic t(9;11) vs v11q23: some clinical trials reported that patients with t(9;11) fared better than patients with v11q23, whereas other studies failed to identify differences. These discrepancies probably reflect the marked biologic heterogeneity of 11q23 aberrations. Furthermore, because many v11q23 translocations are rare translocations, the clinical impact of specific single variants is difficult to extrapolate, even from large studies on 11q23 AL.
Recently, the combined use of conventional cytogenetics, reverse transcriptase-polymerase chain reaction (RT-PCR), Southern blot analysis, and fluorescence in situ hybridization (FISH) in limited AL series has revealed that discrepant results with MLL involvement might become evident, and a high incidence of patients with cryptic MLL+ leukemia were observed in 2 pediatric series. Because the majority of clinical trials include only karyotype data, it is reasonable to speculate that beyond biologic heterogeneity, these discrepancies also are due partly to the low accuracy of conventional cytogenetics.
We describe our findings in a series of 378 consecutive cases of adult AL, studied with conventional cytogenetics, FISH, and multiplex karyotyping (M-FISH) analysis. The aim of the study was to define the incidence of cryptic MLL gene translocation and the incidence of MLL gene rearrangement within 11q22~25+ cases.
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