The MLL recombinome of acute leukemias

Abstract

Chromosomal rearrangements of the human MLL gene are a hallmark for aggressive (high-risk) pediatric, adult and therapyassociated acute leukemias. These patients need to be identified in order to subject these patients to appropriate therapy regimen. A recently developed long-distance inverse PCR method was applied to genomic DNA isolated from individual acute leukemia patients in order to identify chromosomal rearrangements of the human MLL gene. We present data of the molecular characterization of 414 samples obtained from 272 pediatric and 142 adult leukemia patients. The precise localization of genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) was determined and several new TPGs were identified. The combined data of our study and published data revealed a total of 87 different MLL rearrangements of which 51 TPGs are now characterized at the molecular level. Interestingly, the four most frequently found TPGs (AF4, AF9, ENL and AF10) encode nuclear proteins that are part of a protein network involved in histone H3K79 methylation. Thus, translocations of the MLL gene, by itself coding for a histone H3K4 methyltransferase, are presumably not randomly chosen, rather functionally selected.

New insights to the MLL recombinome of acute leukemias

“…On the basis of the results obtained in the present (n ¼ 346) and previous studies (414 patients were already published in 2005 and 2006), 11,12 64 translocation partner genes (TPGs) and their specific breakpoint regions have now been identified. Additional 35 chromosomal translocations of the human MLL gene were characterized by cytogenetics, however, without any further molecular characterization.…”

“…Forty-four fusion genes have been described by others, whereas 20 TPGs have been identified at the Frankfurt DCAL. Additional 35 genetic loci were identified by cytogenetic experiments but not further characterized (for references see Meyer et al 12 ). Five MLL rearrangements were identified that did not display a fusion to an annotated gene or open reading frame.…”

“…11,12 Briefly, 1 mg genomic patient DNA was digested with restriction enzymes and re-ligated to form DNA circles before LDI-PCR analyses. Restriction polymorphic PCR amplimers were isolated from the gel and subjected to DNA sequence analyses to obtain the patient-specific fusion sequences.…”

Leukemia-associated genetic aberrations in mesenchymal stem cells of children with acute lymphoblastic leukemia

“…for the corresponding breakpoint sequence (151). Positive MSC were detected by quantitative real-time PCR and confirmed by DNA-sequence analysis of genomic DNA from blasts and MSC.…”

Acute Monocytic Leukemia with t(11;17)(q23;q21) Involving a Rearrangement of Mixed Lineage Leukemia Gene

“…세포의 복제와 분화를 조절하는 것으로 밝혀져 있고 약 60개의 전 좌 형태가 염색체 분석으로 확인되었으며 약 30개의 MLL 결합 파트너 유전자가 밝혀졌다 [9]. 이중 4개의 MLL 결합파트너 유 전자가 17번 염색체 장완에 존재하는 것으로 보고되었는데 ALL1 fused gene from chromosome 17 (AF17 혹은 MLLT6, 17q21 에 위치), LIM and SH3 protein (LASP1 혹은 MLN50, 17q21 에 위치), MLL septin-like fusion (MSF 혹은 SEPT9, 17q25 에 위치) 및 RARA (17q21에 위치) 유전자이다 [10][11][12][13].…”