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

Patrick R. Blackburn, James B. Smadbeck, Iya Znoyko, Matthew R. Webley, Beth A. Pitel, George Vasmatzis, Xinjie Xu, Patricia T. Greipp, Nicole L. Hoppman, Rhett P. Ketterling, Linda B. Baughn, Kathryn G. Lindsey, Cynthia A. Schandl, Daynna J. Wolff, Jess F. Peterson

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)422-427
Number of pages6
JournalGenes Chromosomes and Cancer
Issue number7
StatePublished - Jul 1 2020


  • B-lymphoblastic leukemia/lymphoma (B-ALL/LBL)
  • KMT2A
  • USP2
  • USP8
  • infant leukemia
  • mixed-phenotype acute leukemia (MPAL)

ASJC Scopus subject areas

  • Genetics
  • Cancer Research


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