Evolution of Human BCR-ABL1 Lymphoblastic Leukaemia-Initiating Cells

Nature. 2011 Jan 20;469(7330):362-7. doi: 10.1038/nature09733.

Abstract

Many tumours are composed of genetically diverse cells; however, little is known about how diversity evolves or the impact that diversity has on functional properties. Here, using xenografting and DNA copy number alteration (CNA) profiling of human BCR-ABL1 lymphoblastic leukaemia, we demonstrate that genetic diversity occurs in functionally defined leukaemia-initiating cells and that many diagnostic patient samples contain multiple genetically distinct leukaemia-initiating cell subclones. Reconstructing the subclonal genetic ancestry of several samples by CNA profiling demonstrated a branching multi-clonal evolution model of leukaemogenesis, rather than linear succession. For some patient samples, the predominant diagnostic clone repopulated xenografts, whereas in others it was outcompeted by minor subclones. Reconstitution with the predominant diagnosis clone was associated with more aggressive growth properties in xenografts, deletion of CDKN2A and CDKN2B, and a trend towards poorer patient outcome. Our findings link clonal diversity with leukaemia-initiating-cell function and underscore the importance of developing therapies that eradicate all intratumoral subclones.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Survival
  • Clone Cells / metabolism*
  • Clone Cells / pathology*
  • Cyclin-Dependent Kinase Inhibitor p15 / deficiency
  • Cyclin-Dependent Kinase Inhibitor p15 / genetics
  • DNA Copy Number Variations / genetics
  • Disease Progression
  • Evolution, Molecular*
  • Fusion Proteins, bcr-abl / genetics*
  • Genes, p16
  • Humans
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Models, Biological
  • Neoplasm Transplantation
  • Oligonucleotide Array Sequence Analysis
  • Philadelphia Chromosome
  • Polymorphism, Single Nucleotide / genetics
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology*
  • Survival Rate
  • Transplantation, Heterologous

Substances

  • Cyclin-Dependent Kinase Inhibitor p15
  • abl-bcr fusion protein, human
  • Fusion Proteins, bcr-abl