KMT2A-MAML2 rearrangement emerged and regressed during neuroblastoma therapy without leukemia after 12.8-year follow-up

Pediatr Blood Cancer. 2022 Jan;69(1):e29344. doi: 10.1002/pbc.29344. Epub 2021 Sep 22.

Abstract

Twelvepatients without therapy-related leukemia were studied after completing TOP2 poison chemotherapy in a high-risk neuroblastoma regimen. One patient harbored an inv(11) that was a KMT2A rearrangement. The KMT2A-MAML2 transcript was expressed at low level. The patient was prospectively followed. The inv(11) was undetectable in ensuing samples. Leukemia never developed after a 12.8-year follow-up period. Enriched etoposide-induced TOP2A cleavage in the relevant MAML2 genomic region supports a TOP2A DNA damage mechanism. After completing TOP2 poison chemotherapies, covert KMT2A-R clones may occur in a small minority of patients; however, not all KMT2A rearrangements herald a therapy-related leukemia diagnosis.

Trial registration: ClinicalTrials.gov NCT00588068.

Keywords: KMT2A-MAML2; TOP2 poison chemotherapy; TOP2A cleave-ome; neuroblastoma; therapy-related leukemia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Etoposide / administration & dosage
  • Follow-Up Studies
  • Gene Rearrangement
  • Histone-Lysine N-Methyltransferase*
  • Humans
  • Leukemia* / genetics
  • Myeloid-Lymphoid Leukemia Protein* / genetics
  • Neuroblastoma* / drug therapy
  • Neuroblastoma* / genetics
  • Trans-Activators*
  • Transcription Factors / genetics

Substances

  • KMT2A protein, human
  • MAML2 protein, human
  • Trans-Activators
  • Transcription Factors
  • Myeloid-Lymphoid Leukemia Protein
  • Etoposide
  • Histone-Lysine N-Methyltransferase

Associated data

  • ClinicalTrials.gov/NCT00588068