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Clonal conversion of B lymphoid leukemia reveals cross-lineage transfer of malignant states

Author:
  • Rajesh Somasundaram
  • Josefine Åhsberg
  • Kazuki Okuyama
  • Jonas Ungerbäck
  • Henrik Lilljebjörn
  • Thoas Fioretos
  • Tobias Strid
  • Mikael Sigvardsson
Publishing year: 2016-11-15
Language: English
Pages: 2486-2499
Publication/Series: Genes and Development
Volume: 30
Issue: 22
Document type: Journal article
Publisher: Cold Spring Harbor Laboratory Press

Abstract english

Even though leukemia is considered to be confined to one specific hematopoietic cell type, cases of acute leukemia of ambiguous lineage and patients relapsing in phenotypically altered disease suggest that a malignant state may be transferred between lineages. Because B-cell leukemia is associated with mutations in transcription factors of importance for stable preservation of lineage identity, we here investigated the potential lineage plasticity of leukemic cells. We report that primary pro-B leukemia cells from mice carrying heterozygous mutations in either or both the Pax5 and Ebf1 genes, commonly mutated in human leukemia, can be converted into T lineage leukemia cells. Even though the conversion process involved global changes in gene expression and lineage-restricted epigenetic reconfiguration, the malignant phenotype of the cells was preserved, enabling them to expand as T lineage leukemia cells in vivo. Furthermore, while the transformed pro-B cells displayed plasticity toward myeloid lineages, the converted cells failed to cause myeloid leukemia after transplantation. These data provide evidence that a malignant phenotype can be transferred between hematopoietic lineages. This has important implications for modern cancer medicine because lineage targeted treatment of leukemia patients can be predicted to provoke the emergence of phenotypically altered subclones, causing clinical relapse.

Keywords

  • Cancer and Oncology
  • Medical Genetics
  • B-ALL
  • Lineage conversion
  • Transcription factors

Other

Published
  • ISSN: 0890-9369
Thoas Fioretos
E-mail: thoas.fioretos [at] med.lu.se

Principal investigator

Division of Clinical Genetics

+46 46 222 45 95

+46 70 334 33 67

BMC C13

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