Open AccessMicroenvironment‐induced PIM kinases promote CXCR 4‐triggered mTOR pathway required for chronic lymphocytic leukaemia cell migration
Author(s) -
Białopiotrowicz Emilia,
Górniak Patryk,
NoyszewskaKania Monika,
Puła Bartosz,
MakuchŁasica Hanna,
Nowak Grażyna,
Bluszcz Aleksandra,
Szydłowski Maciej,
Jabłonska Ewa,
Piechna Karolina,
Sewastianik Tomasz,
Polak Anna,
LechMarańda Ewa,
Budziszewska Bożena K.,
WasyleckaJuszczyńska Maja,
Borg Katarzyna,
Warzocha Krzysztof,
Czardybon Wojciech,
Gałęzowski Michał,
Windak Renata,
Brzózka Krzysztof,
Juszczyński Przemysław
Publication year - 2018
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.13632
Subject(s) - pi3k/akt/mtor pathway , kinase , microbiology and biotechnology , stromal cell , cancer research , phosphorylation , tumor microenvironment , chemistry , signal transduction , biology , tumor cells
Lymph node microenvironment provides chronic lymphocytic leukaemia ( CLL ) cells with signals promoting their survival and granting resistance to chemotherapeutics. CLL cells overexpress PIM kinases, which regulate apoptosis, cell cycle and migration. We demonstrate that BCR crosslinking, CD 40 stimulation, and coculture with stromal cells increases PIM s expression in CLL cells, indicating microenvironment‐dependent PIM s regulation. PIM 1 and PIM 2 expression at diagnosis was higher in patients with advanced disease (Binet C vs. Binet A/B) and in those, who progressed after first‐line treatment. In primary CLL cells, inhibition of PIM kinases with a pan‐ PIM inhibitor, SEL 24‐B489, decreased PIM ‐specific substrate phosphorylation and induced dose‐dependent apoptosis in leukaemic, but not in normal B cells. Cytotoxicity of SEL 24‐B489 was similar in TP 53 ‐mutant and TP 53 wild‐type cells. Finally, inhibition of PIM kinases decreased CXCR 4‐mediated cell chemotaxis in two related mechanisms‐by decreasing CXCR 4 phosphorylation and surface expression, and by limiting CXCR 4‐triggered mTOR pathway activity. Importantly, PIM and mTOR inhibitors similarly impaired migration, indicating that CXCL 12‐triggered mTOR is required for CLL cell chemotaxis. Given the microenvironment‐modulated PIM expression, their pro‐survival function and a role of PIM s in CXCR 4‐induced migration, inhibition of these kinases might override microenvironmental protection and be an attractive therapeutic strategy in this disease.