KMT2A rearranged acute lymphoblastic leukaemia: Unravelling the genomic complexity and heterogeneity of this high-risk disease

Forgione, Michelle O.; McClure, Barbara J.; Eadie, Laura N; Yeung, David T.; White, Deborah L.

doi:10.1016/j.canlet.2019.11.005

Cited by 35 publications

(43 citation statements)

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“…C, DDX3X‐MLLT10 contains the invariably conserved NES of DDX3X, but the EIF4E‐interacting domain required for modulation of translation by DDX3X is often truncated 15 . D, KMT2A‐MLLT10 conserves the N‐terminal domains of KMT2A responsible for protein interactions and non‐specific DNA binding, including the menin‐binding domain, AT hook, subnuclear localization (SNL) domains and CxxC region, but the repression domain (RD) involved in mediation of transcriptional repression is typically truncated 44 . KMT2A‐MLLT10 breakpoints are widely variable, typically located within the 8.3 kb breakpoint cluster region of KMT2A spanning introns 9 to 14, 44 and have been identified across introns 1 to 18 in MLLT10, most frequently introns 8 and 9 45 .…”

Section: Prognosis In Allmentioning

confidence: 99%

“…These findings should be replicated in preclinical models of MLLT10r acute leukemia with clinically relevant HDAC inhibitors such as panobinostat and vorinostat. Other compounds with efficacy in KMT2Ar acute leukemiaKMT2Ar acute leukemia is well-studied, owing to the high incidence across B-ALL, T-ALL and AML (approximately 6%-7% in each disease subtype44 ), including a high proportion of infant diagnoses, and this subtype confers very poor outcomes across all ages 95. Many therapeutic agents have preclinical efficacy in KMT2Ar acute leukemia, and the high similarity in gene expression profiles of KMT2Ar and MLLT10r acute leukemia suggest that these therapeutic targets may be effective in treating patients with MLLT10r.…”

mentioning

confidence: 99%

“…D, KMT2A-MLLT10 conserves the N-terminal domains of KMT2A responsible for protein interactions and non-specific DNA binding, including the menin-binding domain, AT hook, subnuclear localization (SNL) domains and CxxC region, but the repression domain (RD) involved in mediation of transcriptional repression is typically truncated 44. KMT2A-MLLT10 breakpoints are widely variable, typically located within the 8.3 kb breakpoint cluster region of KMT2A spanning introns 9 to 14,44 and have been identified across introns 1 to 18 in MLLT10, most frequently introns 8 and 9 45. [Color figure can be viewed at wileyonlinelibrary.com] suggesting activation of common pathways in both subtypes.…”

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confidence: 99%

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MLLT10 rearranged acute leukemia: Incidence, prognosis, and possible therapeutic strategies

Forgione

McClure

Yeung

et al. 2020

Genes Chromosomes & Cancer

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Rearrangements of the MLLT10 gene occur in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), most commonly T-lineage ALL (T-ALL), in patients of all ages. MLLT10 rearranged (MLLT10r) acute leukemia presents a complex diagnostic and therapeutic challenge due to frequent presentation of immature or mixed phenotype, and a lack of consensus regarding optimal therapy. Cases of MLLT10r AML or TALL bearing immature phenotype are at high risk of poor outcome, but the underlying molecular mechanisms and sensitivity to targeted therapies remain poorly characterized. This review addresses the incidence and prognostic significance of MLLT10r in acute leukemia, and how the aberrant gene expression profile of this disease can inform potential targeted therapeutic strategies. Understanding the underlying genomics of MLLT10r acute leukemia, both clinically and molecularly, will improve prognostic stratification and accelerate the development of targeted therapeutic strategies, to improve patient outcomes.

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Section: Prognosis In Allmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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MLLT10 rearranged acute leukemia: Incidence, prognosis, and possible therapeutic strategies

Forgione

McClure

Yeung

et al. 2020

Genes Chromosomes & Cancer

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“…Typical KMT2A fusions result in an in-frame linkage with a TPG with retention of the 5 0 end of KMT2A. 1,9,10 Breaks most frequently occur within a common breakpoint region local-region with some, like the KMT2A-USP2 fusion mentioned above, clustering in a minor breakpoint region between intron 19 and exon 24. 6 Less commonly KMT2A fusions are fused out-of-frame to a C-terminal TPG or lack sequences that encode for a TPG.…”

Section: Discussionmentioning

confidence: 99%

“…9,10 Regions in the N-terminal portion of the protein entail DNA and transcription factor binding and subnuclear localization whereas the C-terminal part mediates the function of the gene product, primarily histone 3 lysine 4 methylation (H3K4me) of target genes. 9,10 Classic KMT2A-TPGs dissociate the DNA and transcriptional factor binding regions from functional domains of the protein. 9 Fusion partners are diverse and some direct altered functions of the chimaeric molecule.…”

Section: Discussionmentioning

confidence: 99%

Reciprocal ATP5L–KMT2A gene fusion in a paediatric B lymphoblastic leukaemia/lymphoma (B‐ALL) patient

et al. 2020

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Gene rearrangements involving the histone lysine methyltransferase 2A gene (KMT2A) are identified in 4-7% of childhood acute lymphoblastic leukaemias (ALL). 1 The rearrangement is associated with a poor prognosis, presentation in infancy and lymphoblasts lacking CD10 with expression of myeloid markers. 2-4 KMT2A fusions are promiscuous with 135 different transfusion partner genes (TPGs) reported. 1 The vast majority fuse the 5 0 end of KMT2A in-frame to a TPG at the 3 0 end. 1 However, reciprocal translocations (TPG-KMT2A) are also found either in association with KMT2A-TPG fusions or rarely, in some instances, by themselves without a corresponding KMT2A-TPG fusion. 1 Here, we describe an isolated ATP5L-KMT2A reciprocal fusion in a 15-month-old male with B lymphoblastic leukaemia/lymphoma (B-ALL). The University Hospitals Cleveland Medical Center/Case Western Reserve University's Institutional Review Board granted approval for the study under number #02-14-36. The patient presented at 14 months in Kuwait with refusal to walk, malaise and fevers. A complete blood count demonstrated: white blood cells 22Á4 9 10 9 /l, haemoglobin 75 g/l, platelets 24 9 10 9 /l. A bone marrow work-up revealed 91Á5% blasts. Phenotypically, the cells were CD10 À , CD19 + , CD20 À , CD34 + , CD45 dim , TdT + (partial) and MPOconsistent with BALL. Genetic studies showed a normal karyotype and fluorescent in situ hybridization (FISH) was negative for t(12;21) (p13;q22), t(9;22)(q34;q11), t(1;19)(q23;p13Á3) and KMT2A (11q23) rearrangements. The patient was classified as standard risk BALL and received three-drug induction therapy per UK-MRC-ALL 2011. On day 15 of induction, persistent blasts (66%) were present and treatment was intensified to include anthracyclines and an additional dose of PEG asparaginase. He was transferred to our institution after completing induction therapy. Persistent disease was noted upon arrival at our institution with 48% marrow blasts with a phenotype as previously reported (Fig 1A, B). Repeat FISH for KMT2A rearrangement was negative with two yellow signals suggesting two intact copes of the KMT2A gene (Fig 1C). To further evaluate for a molecular aberration, cells were assessed for novel gene fusions using a NeoGenomics (Fort Myers, FL, USA) ALL fusion profile which identified an ATP5L-KMT2A fusion (Fig 2), discussed below. He received consolidation therapy for very high-risk BALL patients per COG AALL1131 followed by two cycles of blinatumomab. Subsequently he underwent a matched, unrelated umbilical cord transplant and presently is seven months post-transplant and disease-free. ized to exons 9-11 of the KMT2A gene 1. Only 6Á5% of KMT2A fusions occur with breakpoints outside of this Correspondence

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Proximally biased V(D)J recombination in the clonal evolution of IGH alleles in KMT2A::AFF1 BCP‐ALL of all age classes

Müller,

Dicker,

Bär

et al. 2024

HemaSphere

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KMT2A rearranged acute lymphoblastic leukaemia: Unravelling the genomic complexity and heterogeneity of this high-risk disease

Cited by 35 publications

References 100 publications

MLLT10 rearranged acute leukemia: Incidence, prognosis, and possible therapeutic strategies

MLLT10 rearranged acute leukemia: Incidence, prognosis, and possible therapeutic strategies

Reciprocal ATP5L–KMT2A gene fusion in a paediatric B lymphoblastic leukaemia/lymphoma (B‐ALL) patient

Proximally biased V(D)J recombination in the clonal evolution of IGH alleles in KMT2A::AFF1 BCP‐ALL of all age classes

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