Twins with different personalities: STAT5B-but not STAT5A-has a key role in BCR/ABL-induced leukemia.

Leukemia 2019 07 24;33(7):1583-1597. Epub 2019 Jan 24.

Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, 1210, Vienna, Austria.

Deregulation of the Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway is found in cancer with STAT5A/B controlling leukemic cell survival and disease progression. As mutations in STAT5B, but not STAT5A, have been frequently described in hematopoietic tumors, we used BCR/ABL as model systems to investigate the contribution of STAT5A or STAT5B for leukemogenesis. The absence of STAT5A decreased cell survival and colony formation. Even more drastic effects were observed in the absence of STAT5B. STAT5B-deficient cells formed BCR/ABL colonies or stable cell lines at low frequency. The rarely evolving Stat5b cell lines expressed enhanced levels of BCR/ABL oncoprotein compared to wild-type cells. In line, Stat5b leukemic cells induced leukemia with a significantly prolonged disease onset, whereas Stat5a cells rapidly caused a fatal disease superimposable to wild-type cells. RNA-sequencing (RNA-seq) profiling revealed a marked enhancement of interferon (IFN)-α and IFN-γ signatures in Stat5b cells. Inhibition of IFN responses rescued BCR/ABL colony formation of Stat5b-deficient cells. A downregulated IFN response was also observed in patients suffering from leukemia carrying STAT5B mutations. Our data define STAT5B as major STAT5 isoform driving BCR/ABL leukemia. STAT5B enables transformation by suppressing IFN-α/γ, thereby facilitating leukemogenesis. Our findings might help explain the high frequency of STAT5B mutations in hematopoietic tumors.

Download full-text PDF

Source
http://www.nature.com/articles/s41375-018-0369-5
Publisher Site
http://dx.doi.org/10.1038/s41375-018-0369-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6755975PMC
July 2019
27 Reads

Publication Analysis

Top Keywords

stat5b
10
cell lines
8
colony formation
8
wild-type cells
8
hematopoietic tumors
8
stat5b mutations
8
cell survival
8
stat5b-deficient cells
8
cells
7
bcr/abl
5
onset stat5a
4
disease onset
4
stat5a cells
4
induced leukemia
4
prolonged disease
4
leukemia prolonged
4
fatal disease
4
cells rna-sequencing
4
rna-sequencing rna-seq
4
rna-seq profiling
4

References

(Supplied by CrossRef)

JJ O’Shea et al.
N Engl J Med 2013

RL Levine et al.
Nat Rev Cancer 2007

LS Steelman et al.
Leukemia 2004

H Yu et al.
Nat Rev Cancer 2004

J Schwaller et al.
Mol Cell 2000

RL Ilaria et al.
J Biol Chem 1996

K Spiekermann et al.
Exp Hematol 2002

A Hoelbl et al.
Blood 2006

A Hoelbl et al.
EMBO Mol Med 2010

X Liu et al.
Genes Dev 1997

D Yamaji et al.
Genes Dev 2009

Similar Publications