The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias.

Research output: Contribution to journalArticle

Abstract

Infant acute lymphoblastic leukemia (ALL) with MLL rearrangements (MLL-R) represents a distinct leukemia with a poor prognosis. To define its mutational landscape, we performed whole-genome, exome, RNA and targeted DNA sequencing on 65 infants (47 MLL-R and 18 non-MLL-R cases) and 20 older children (MLL-R cases) with leukemia. Our data show that infant MLL-R ALL has one of the lowest frequencies of somatic mutations of any sequenced cancer, with the predominant leukemic clone carrying a mean of 1.3 non-silent mutations. Despite this paucity of mutations, we detected activating mutations in kinase-PI3K-RAS signaling pathway components in 47% of cases. Surprisingly, these mutations were often subclonal and were frequently lost at relapse. In contrast to infant cases, MLL-R leukemia in older children had more somatic mutations (mean of 6.5 mutations/case versus 1.3 mutations/case, P = 7.15 × 10(-5)) and had frequent mutations (45%) in epigenetic regulators, a category of genes that, with the exception of MLL, was rarely mutated in infant MLL-R ALL.

Details

Authors
  • Jing Ma
  • Jianmin Wang
  • Xiang Chen
  • Amanda Larson Gedman
  • Jinjun Dang
  • Joy Nakitandwe
  • Linda Holmfeldt
  • Matthew Parker
  • John Easton
  • Robert Huether
  • Richard Kriwacki
  • Michael Rusch
  • Gang Wu
  • Yongjin Li
  • Heather Mulder
  • Susana Raimondi
  • Stanley Pounds
  • Guolian Kang
  • Lei Shi
  • Jared Becksfort
  • Pankaj Gupta
  • Debbie Payne-Turner
  • Bhavin Vadodaria
  • Kristy Boggs
  • Donald Yergeau
  • Jayanthi Manne
  • Guangchun Song
  • Michael Edmonson
  • Panduka Nagahawatte
  • Lei Wei
  • Cheng Cheng
  • Deqing Pei
  • Rosemary Sutton
  • Nicola C Venn
  • Albert Chetcuti
  • Amanda Rush
  • Daniel Catchpoole
  • Jesper Heldrup
  • Charles Lu
  • Li Ding
  • Ching-Hon Pui
  • Sheila Shurtleff
  • Charles G Mullighan
  • Elaine R Mardis
  • Richard K Wilson
  • Tanja A Gruber
  • Jinghui Zhang
  • James R Downing
Organisations
External organisations
  • Skåne University Hospital
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medical Genetics
Original languageEnglish
Pages (from-to)330-U192
JournalNature Genetics
Volume47
Issue number4
Publication statusPublished - 2015
Publication categoryResearch
Peer-reviewedYes