Human MLL/KMT2A gene exhibits a second breakpoint cluster region for recurrent MLL–USP2 fusions

Meyer, Claus; Lopes, Bruno A.; Caye-Eude, Aurélie; Cavé, Hélène; Arfeuille, Chloé; Cuccuini, Wendy; Sutton, Rosemary; Venn, Nicola C.; Oh, Seung Hwan; Tsaur, Grigory; Escherich, Gabriele; Feuchtinger, Tobias; Kosasih, Hansen J; Khaw, Seong Lin; Ekert, Paul G.; Pombo‐de‐Oliveira, Maria S.; Bidet, Audrey; Djahanschiri, Bardya; Ebersberger, Ingo; Žaliová, Markéta; Zuna, Jan; Zermanova, Zuzana; Juvonen, Vesa; Grümayer, R.; Fazio, Grazia; Cazzaniga, Giovanni; Larghero, Patrizia; Emerenciano, Mariana; Marschalek, Rolf

doi:10.1038/s41375-019-0451-7

Cited by 45 publications

(74 citation statements)

References 14 publications

(14 reference statements)

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“…DNA was processed using Illumina Nextera Mate Pair library kit (Illumina, San Diego, CA), multiplexed at two samples per lane, and sequenced on the Illumina HiSeq 2500 on Rapid run mode. Data were aligned to the reference genome (GRCh38) using BIMAv3, and abnormalities were identified and visualized using SVAtools and Ingenium, both in‐house developed bioinformatics tools 14 …”

Section: Methodsmentioning

confidence: 99%

“…In the largest cohort to date, Meyer et al identified KMT2A‐USP2 gene fusions in 17 pediatric patients using a custom NGS panel 5,12,13 . Twelve cases were classified as B‐ALL, four cases as MPAL (B/myeloid), and a single case had AML, with a median age at diagnosis of 17 months overall 14 . Most patients presented with leukocytosis, approximately 30% of patients presented with extramedullary CNS involvement, and a majority had poor responses to frontline treatment consistent with high‐risk disease 14 .…”

Section: Introductionmentioning

confidence: 99%

“…Twelve cases were classified as B‐ALL, four cases as MPAL (B/myeloid), and a single case had AML, with a median age at diagnosis of 17 months overall 14 . Most patients presented with leukocytosis, approximately 30% of patients presented with extramedullary CNS involvement, and a majority had poor responses to frontline treatment consistent with high‐risk disease 14 . Importantly, ~45% of cases had cryptic KMT2A‐USP2 rearrangements that were undetectable using routine cytogenetic techniques 14 …”

Section: Introductionmentioning

confidence: 99%

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Cryptic and atypical KMT2A‐USP2 and KMT2A‐USP8 rearrangements identified by mate pair sequencing in infant and childhood leukemia

Blackburn

Smadbeck

Znoyko

et al. 2020

Genes Chromosomes & Cancer

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Infant leukemias are a rare group of neoplasms that are clinically and biologically distinct from their pediatric and adult counterparts. Unlike leukemia in older children where survival rates are generally favorable, infants with leukemia have a 5-year eventfree survival rate of <50%. The majority of infant leukemias are characterized by KMT2A (MLL) rearrangements (~70 to 80% in acute lymphoblastic leukemia), which appear to be drivers of early leukemogenesis. In this report, we describe three cases: a 9-month-old female infant with B-acute lymphoblastic leukemia (B-ALL), an 8-month-old female presenting with B/myeloid mixed phenotype acute leukemia (MPAL), and a 16-month-old male with B-ALL. The first case had a normal karyotype and B-ALL FISH results consistent with an atypical KMT2A rearrangement. The second case had trisomy 10 as the sole chromosomal abnormality and a normal KMT2A FISH result. Case 3 had trisomy 8 and a t (11;15)(q23;q21), an atypical KMT2A rearrangement by FISH studies, and a focal deletion of 15q with a breakpoint within the USP8 gene by chromosomal microarray. Mate pair sequencing was performed on all three cases and identified a KMT2A-USP2 rearrangement (cases 1 and 2) or a KMT2A-USP8 rearrangement (case 3). These recently characterized KMT2A fusions have been described exclusively in infant and pediatric leukemia cases where the incidence varies vary according to leukemia subtype, are considered high-risk, with a high incidence of central nervous system involvement, poor response to initial prednisone treatment, and poor event free survival. Additionally, approximately half of cases are unable to be resolved using standard cytogenetic approaches and are likely under recognized. Therefore, targeted molecular approaches are suggested in genetically unresolved infant leukemia cases to characterize these prognostically relevant clones. K E Y W O R D S B-lymphoblastic leukemia/lymphoma (B-ALL/LBL), infant leukemia, KMT2A, mixed-phenotype acute leukemia (MPAL), USP2, USP8

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Cryptic and atypical KMT2A‐USP2 and KMT2A‐USP8 rearrangements identified by mate pair sequencing in infant and childhood leukemia

Blackburn

Smadbeck

Znoyko

et al. 2020

Genes Chromosomes & Cancer

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show abstract

“…For the AML sample, diagnostic efforts identified a KMT2A fusion through break-apart FISH; however, the fusion partner could not be identified. The KMT2A gene is a frequent fusion partner in AML and ALL and shows two major breakpoint clusters 4 for both of which we designed crRNAs (Suppl. Fig.…”

Section: Detection Of Fusion Genes From Tumor Materialsmentioning

confidence: 99%

“…children <1 year of age), and has been reported with more than 130 different gene configurations 4,5 .…”

Section: Introductionmentioning

confidence: 99%

Partner-independent fusion gene detection by multiplexed CRISPR/Cas9 enrichment and long-read Nanopore sequencing

Stangl

Blank

Renkens

et al. 2019

Preprint

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Fusion genes are hallmarks of various cancer types and important determinants for diagnosis, prognosis and treatment possibilities. The promiscuity of fusion genes with respect to partner choice and exact breakpoint-positions restricts their detection in the diagnostic setting, even for known and recurrent fusion gene configurations. To accurately identify these gene fusions in an unbiased manner, we developed FUDGE: a FUsion gene Detection assay from Gene Enrichment. FUDGE couples target-selected and strand-specific CRISPR/Cas9 activity for enrichment and detection of fusion gene drivers (e.g. BRAF, EWSR1, KMT2A/MLL) -without prior knowledge of fusion partner or breakpoint-location -to long-read Nanopore sequencing.FUDGE encompasses a dedicated bioinformatics approach (NanoFG) to detect fusion genes from Nanopore sequencing data. Our strategy is flexible with respect to target choice and enables multiplexed enrichment for simultaneous analysis of several genes in multiple samples in a single sequencing run. We observe on average a 508 fold on-target enrichment and identify fusion breakpoints at nucleotide resolution -all within two days. We demonstrate that FUDGE effectively identifies fusion genes in cancer cell lines, tumor samples and on whole genome amplified DNA irrespective of partner gene or breakpoint-position in 100% of cases. Furthermore, we show that FUDGE is superior to routine diagnostic methods for fusion gene detection. In summary, we have developed a rapid and versatile fusion gene detection assay, providing an unparalleled opportunity for pan-cancer detection of fusion genes in routine diagnostics.

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Leukemia‐associated transcription factor mllt3 is important for primitive erythroid development in zebrafish embryogenesis

Germanò

Porazzi

Felix

2022

Developmental Dynamics

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Background: MLLT3 (AF9) is a nuclear transcription factor crucial for hematopoietic stem cell and progenitor cell maintenance, but its role during embryonic hematopoiesis remains uncertain. Here, we examine the role of mllt3 in developmental hematopoiesis during embryogenesis using zebrafish.Results: Cloning, sequencing, phylogenetic, and synteny analyses showed high evolutionary conservation between important functional domains of the zebrafish orthologue of mllt3 and MLLT3 in humans. Quantitative reverse transcription-PCR and in situ hybridization analyses revealed that mllt3 is maternally supplied and zygotically expressed throughout embryonic development, and that expression is highest between 10 and 24 hours postfertilization (hpf) coincident with enrichment in the intermediate cell mass (ICM) and posterior blood island, which are the sites of the primitive and transient definitive hematopoiesis in zebrafish, respectively. Further, we found co-expression of mllt3 with the early hematopoietic progenitor markers tal1, gata2, and gata1a in the posterior ICM. By investigating zebrafish hematopoietic mutants, we discovered that mllt3 is involved in erythroid precursor formation. By 48-72 hpf, mllt3 expression proved to be restricted to non-hematopoietic tissues including head structures, pronephric tubules, and liver primordium. Conclusions: These findings establish a link between mllt3 and primitive erythropoiesis and provide the basis for future functional investigations.

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Human MLL/KMT2A gene exhibits a second breakpoint cluster region for recurrent MLL–USP2 fusions

Cited by 45 publications

References 14 publications

Cryptic and atypical KMT2A‐USP2 and KMT2A‐USP8 rearrangements identified by mate pair sequencing in infant and childhood leukemia

Cryptic and atypical KMT2A‐USP2 and KMT2A‐USP8 rearrangements identified by mate pair sequencing in infant and childhood leukemia

Partner-independent fusion gene detection by multiplexed CRISPR/Cas9 enrichment and long-read Nanopore sequencing

Leukemia‐associated transcription factor mllt3 is important for primitive erythroid development in zebrafish embryogenesis

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