Chromosomal rearrangements of the human KMT2A/MLL gene are associated with de novo as well as therapy-induced infant, pediatric, and adult acute leukemias. Here, we present the data obtained from 3401 acute leukemia patients that have been analyzed between 2003 and 2022. Genomic breakpoints within the KMT2A gene and the involved translocation partner genes (TPGs) and KMT2A-partial tandem duplications (PTDs) were determined. Including the published data from the literature, a total of 107 in-frame KMT2A gene fusions have been identified so far. Further 16 rearrangements were out-of-frame fusions, 18 patients had no partner gene fused to 5'-KMT2A, two patients had a 5'-KMT2A deletion, and one ETV6::RUNX1 patient had an KMT2A insertion at the breakpoint. The seven most frequent TPGs and PTDs account for more than 90% of all recombinations of the KMT2A, 37 occur recurrently and 63 were identified so far only once. This study provides a comprehensive analysis of the KMT2A recombinome in acute leukemia patients. Besides the scientific gain of information, genomic breakpoint sequences of these patients were used to monitor minimal residual disease (MRD). Thus, this work may be directly translated from the bench to the bedside of patients and meet the clinical needs to improve patient survival.

• MeSH
• akutní lymfatická leukemie * genetika   MeSH
• akutní myeloidní leukemie * genetika   MeSH
• dítě MeSH
• dospělí MeSH
• fúze genů MeSH
• histonlysin-N-methyltransferasa * genetika   MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• předškolní dítě MeSH
• protoonkogenní protein MLL * genetika   MeSH
• senioři MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• předškolní dítě MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Minimal residual disease (MRD) is a powerful prognostic factor in acute lymphoblastic leukemia (ALL) and is used for patient stratification and treatment decisions, but its precise role in Philadelphia chromosome positive ALL is less clear. This uncertainty results largely from methodological differences relating to the use of real-time quantitative PCR (qRT-PCR) to measure BCR-ABL1 transcript levels for MRD analysis. We here describe the first results by the EURO-MRD consortium on standardization of qRT-PCR for the e1a2 BCR-ABL1 transcript in Ph + ALL, designed to overcome the lack of standardisation of laboratory procedures and data interpretation. Standardised use of EAC primer/probe sets and of centrally prepared plasmid standards had the greatest impact on reducing interlaboratory variability. In QC1 the proportion of analyses with BCR-ABL1/ABL1 ratios within half a log difference were 40/67 (60%) and 52/67 (78%) at 10-3 and 36/67 (53%) and 53/67 (79%) at 10-4BCR-ABL1/ABL1. Standardized RNA extraction, cDNA synthesis and cycler platforms did not improve results further, whereas stringent application of technical criteria for assay quality and uniform criteria for data interpretation and reporting were essential. We provide detailed laboratory recommendations for the standardized MRD analysis in routine diagnostic settings and in multicenter clinical trials for Ph + ALL.

• MeSH
• akutní lymfatická leukemie genetika   MeSH
• bcr-abl fúzové proteiny genetika   MeSH
• filadelfský chromozom * MeSH
• konsensus MeSH
• kvantitativní polymerázová řetězová reakce metody   MeSH
• lidé MeSH
• messenger RNA analýza   MeSH
• reziduální nádor MeSH
• směrnice pro lékařskou praxi jako téma * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Chromosomal rearrangements of the human MLL/KMT2A gene are associated with infant, pediatric, adult and therapy-induced acute leukemias. Here we present the data obtained from 2345 acute leukemia patients. Genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and 11 novel TPGs were identified. Thus, a total of 135 different MLL rearrangements have been identified so far, of which 94 TPGs are now characterized at the molecular level. In all, 35 out of these 94 TPGs occur recurrently, but only 9 specific gene fusions account for more than 90% of all illegitimate recombinations of the MLL gene. We observed an age-dependent breakpoint shift with breakpoints localizing within MLL intron 11 associated with acute lymphoblastic leukemia and younger patients, while breakpoints in MLL intron 9 predominate in AML or older patients. The molecular characterization of MLL breakpoints suggests different etiologies in the different age groups and allows the correlation of functional domains of the MLL gene with clinical outcome. This study provides a comprehensive analysis of the MLL recombinome in acute leukemia and demonstrates that the establishment of patient-specific chromosomal fusion sites allows the design of specific PCR primers for minimal residual disease analyses for all patients.

• MeSH
• akutní lymfatická leukemie genetika   MeSH
• akutní myeloidní leukemie genetika   MeSH
• chromozomální aberace MeSH
• dítě MeSH
• dospělí MeSH
• fúzní onkogenní proteiny genetika   MeSH
• genová přestavba genetika   MeSH
• histonlysin-N-methyltransferasa genetika   MeSH
• kojenec MeSH
• lidé MeSH
• protoonkogenní protein MLL genetika   MeSH
• translokace genetická genetika   MeSH
• zlomy chromozomů MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• akutní lymfatická leukemie genetika   patologie   MeSH
• delece genu * MeSH
• dítě MeSH
• filadelfský chromozom * MeSH
• jednonukleotidový polymorfismus genetika   MeSH
• kohortové studie MeSH
• lidé MeSH
• mutace genetika   MeSH
• nádorové biomarkery genetika   MeSH
• prognóza MeSH
• sekvenční analýza DNA MeSH
• transkripční faktor Ikaros genetika   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• Publikační typ
• dopisy MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH

• Publikační typ
• abstrakt z konference MeSH

Data on secondary acute lymphoblastic leukaemia (sALL) following ALL treatment are very rare. However, the incidence might be underestimated as sALLs without a significant lineage shift might automatically be diagnosed as relapses. Examination of immunoglobulin and T-cell receptor gene rearrangements brought a new tool that can help in discrimination between relapse and sALL. We focused on the recurrences of childhood ALL to discover the real frequency of the sALL after ALL treatment. We compared clonal markers in matched presentation and recurrence samples of 366 patients treated according to the Berlin-Frankfurt-Munster (BFM)-based protocols. We found two cases of sALL and another three, where the recurrence is suspicious of being sALL rather than relapse. Our proposal for the 'secondary ALL after ALL' diagnostic criteria is as follows: (A) No clonal relationship between diagnosis and recurrence; (B) significant immunophenotypic shift--significant cytogenetic shift--gain/loss of a fusion gene. For the sALL (A) plus at least one (B) criterion should be fulfilled. With these criteria, the estimated frequency of the sALL after ALL is according to our data 0.5-1.5% of ALL recurrences on BFM-based protocols. Finally, we propose a treatment strategy for the patients with secondary disease.

• MeSH
• akutní lymfatická leukemie diagnóza   farmakoterapie   chemicky indukované   MeSH
• antitumorózní látky škodlivé účinky   MeSH
• diagnostické techniky molekulární metody   MeSH
• diferenciální diagnóza MeSH
• financování organizované MeSH
• genová přestavba T-lymfocytů MeSH
• geny pro imunoglobuliny MeSH
• imunofenotypizace MeSH
• incidence MeSH
• lidé MeSH
• předškolní dítě MeSH
• recidiva MeSH
• sekundární malignity diagnóza   chemicky indukované   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH