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

Genes Chromosomes Cancer. 2020 Jul;59(7):422-427. doi: 10.1002/gcc.22842. Epub 2020 Mar 26.


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 event-free 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.

Keywords: KMT2A; USP2; USP8; B-lymphoblastic leukemia/lymphoma (B-ALL/LBL); infant leukemia; mixed-phenotype acute leukemia (MPAL).

Publication types

  • Case Reports

MeSH terms

  • Endopeptidases / genetics
  • Endosomal Sorting Complexes Required for Transport / genetics
  • Female
  • Gene Rearrangement*
  • Genetic Testing / methods
  • Histone-Lysine N-Methyltransferase / genetics*
  • Humans
  • Infant
  • Male
  • Myeloid-Lymphoid Leukemia Protein / genetics*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • Ubiquitin Thiolesterase / genetics


  • Endosomal Sorting Complexes Required for Transport
  • KMT2A protein, human
  • Myeloid-Lymphoid Leukemia Protein
  • Histone-Lysine N-Methyltransferase
  • Endopeptidases
  • USP2 protein, human
  • USP8 protein, human
  • Ubiquitin Thiolesterase