Article (Scientific journals)
Overexpression of SH2-containing inositol phosphatase contributes to chronic lymphocytic leukemia survival
Pal Singh, Simar; de Bruijn, Marjolein J. W.; Velaso Gago da Graça, Catarina et al.
2020In Journal of Immunology, 204, p. 360-374
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Keywords :
Ship2; Inppl1; leukemia; Chronic lymphocytic leukemia; Akt/mTORC1/S6 signaling; BCR signaling; Btk
Abstract :
[en] Balanced activity of kinases and phosphatases downstream of the BCR is essential for B cell differentiation and function and is disturbed in chronic lymphocytic leukemia (CLL). In this study, we employed IgH.TEμ mice, which spontaneously develop CLL, and stable EMC CLL cell lines derived from these mice to explore the role of phosphatases in CLL. Genome-wide expression profiling comparing IgH.TEμ CLL cells with wild-type splenic B cells identified 96 differentially expressed phosphatase genes, including SH2-containing inositol phosphatase (Ship2). We found that B cell-specific deletion of Ship2, but not of its close homolog Ship1, significantly reduced CLL formation in IgH.TEμ mice. Treatment of EMC cell lines with Ship1/2 small molecule inhibitors resulted in the induction of caspase-dependent apoptosis. Using flow cytometry and Western blot analysis, we observed that blocking Ship1/2 abrogated EMC cell survival by exerting dual effects on the BCR signaling cascade. On one hand, specific Ship1 inhibition enhanced calcium signaling and thereby abrogated an anergic response to BCR stimulation in CLL cells. On the other hand, concomitant Ship1/Ship2 inhibition or specific Ship2 inhibition reduced constitutive activation of the mTORC1/ribosomal protein S6 pathway and downregulated constitutive expression of the antiapoptotic protein Mcl-1, in both EMC cell lines and primary IgH.TEμ CLL cells. Importantly, also in human CLL, we found overexpression of many phosphatases including SHIP2. Inhibition of SHIP1/SHIP2 reduced cellular survival and S6 phosphorylation and enhanced basal calcium levels in human CLL cells. Taken together, we provide evidence that SHIP2 contributes to CLL pathogenesis in mouse and human CLL.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Pal Singh, Simar
de Bruijn, Marjolein J. W.
Velaso Gago da Graça, Catarina
Cornet, Odilia B. J.
Rip, Jasper
Stadhouders, Ralph
Meijers, Ruud W. J.
Schurmans, Stéphane  ;  Université de Liège - ULiège > Département des sciences fonctionnelles (DSF) > Biochimie métabolique vétérinaire
Kerr, William G.
ter Burg, Johanna
Eldering, Eric
Langerak, Anton W.
Pillai, Saravanan Y.
Hendriks, Rudi W.
More authors (4 more) Less
Language :
English
Title :
Overexpression of SH2-containing inositol phosphatase contributes to chronic lymphocytic leukemia survival
Publication date :
2020
Journal title :
Journal of Immunology
ISSN :
0022-1767
eISSN :
1550-6606
Publisher :
American Association of Immunologists, United States - Maryland
Volume :
204
Pages :
360-374
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 13 November 2019

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