Advanced

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

Somasundaram, Rajesh; Åhsberg, Josefine LU ; Okuyama, Kazuki; Ungerbäck, Jonas; Lilljebjörn, Henrik LU ; Fioretos, Thoas LU ; Strid, Tobias LU and Sigvardsson, Mikael LU (2016) In Genes and Development 30(22). p.2486-2499
Abstract

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... (More)

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.

(Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
B-ALL, Lineage conversion, Transcription factors
in
Genes and Development
volume
30
issue
22
pages
14 pages
publisher
Cold Spring Harbor Laboratory Press
external identifiers
  • scopus:85005993346
  • wos:000390615700003
ISSN
0890-9369
DOI
10.1101/gad.285536.116
language
English
LU publication?
yes
id
1e60d1c5-28df-4a96-a557-f9d8cd717b6e
date added to LUP
2016-12-30 09:27:20
date last changed
2017-09-18 11:34:35
@article{1e60d1c5-28df-4a96-a557-f9d8cd717b6e,
  abstract     = {<p>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.</p>},
  author       = {Somasundaram, Rajesh and Åhsberg, Josefine and Okuyama, Kazuki and Ungerbäck, Jonas and Lilljebjörn, Henrik and Fioretos, Thoas and Strid, Tobias and Sigvardsson, Mikael},
  issn         = {0890-9369},
  keyword      = {B-ALL,Lineage conversion,Transcription factors},
  language     = {eng},
  month        = {11},
  number       = {22},
  pages        = {2486--2499},
  publisher    = {Cold Spring Harbor Laboratory Press},
  series       = {Genes and Development},
  title        = {Clonal conversion of B lymphoid leukemia reveals cross-lineage transfer of malignant states},
  url          = {http://dx.doi.org/10.1101/gad.285536.116},
  volume       = {30},
  year         = {2016},
}