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

Abstract

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

Rearrangements of ATP5L‐KMT2A in acute lymphoblastic leukaemia

“…Thanks to the use of transcriptome sequencing approaches, new cryptic fusion transcripts have been described, such as the ATP5L‐KMT2A gene fusion, described by Gestrich et al . in a 14‐month‐old patient with aggressive B‐ALL 5 . ATP5L or ATP5MG (ATP Synthase Membrane Subunit G) catalyzes ATP synthesis during oxidative phosphorylation 6 .…”

“…In agreement with the data published in the above mentioned study, ATP5L exon 1‐ KMT2A exon 2 resulted in a premature stop codon immediately two nucleotides after the breakpoint site, at the beginning of KMT2A exon 2 (Fig 1B). 5 The transcript, including ATP5L exon 2 fused to KMT2A exon 2, resulted in an in‐frame fusion that preserved ATP5L and KMT2A coding frames (Fig 1B).…”

“…Because of the diagnostic, prognostic and clinical importance of KMT2A rearranged fusions, here we investigated the frequency of the recently reported ATP5L‐KMT2A fusion 5 . The rearrangement ATP5L exon 1‐ KMT2A exon 2 (i) was not caused by detectable deletions between the two adjacent genes; (ii) was not predicted to encode a functional protein; and (iii) was commonly found in 100% of ALL cases, 71·4% of solid tumor and 83·3% of donor samples.…”

“…ATP5L is a novel KMT2A fusion partner not detectable by fluorescent in situ hybridization (FISH) or karyotype, due to the closeness of the two genes on chromosome 11q23. The Cleveland Medical Centre team found a reciprocal out‐of‐frame ATP5L‐KMT2A rearrangement that juxtaposes the ATP5L exon 1 to the KMT2A exon 2, with the insertion of an extra nucleotide (G) at the fusion site 5 . We sequenced leukaemic cells from eight adult ALL patients (two T‐ALL, five B‐ALL Philadelphia negative (Ph−) and one B‐ALL Ph+; Table I) by a 199 gene RNA‐sequencing panel (RNA‐seq; Pan‐Heme FusionPlex, ArcherDx Inc., Boulder, CO, USA).…”

Potential of ATP5MG to Treat Metabolic Syndrome-Associated Cardiovascular Diseases

“…ATP5L may act as a marker of oncogenic cell transformation ( 14) and be upregulated using orchiectomy in the substantia nigra in aged males (15). Additionally, ATP5L-KMT2A gene fusion presents in leukemia (16,17). It can be seen from the above examinations that the association between ATP5MG and MetS-CVD development has not been shown.…”