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CXCR 4 WHIM ‐like frameshift and nonsense mutations promote ibrutinib resistance but do not supplant MYD 88 L265P ‐directed survival signalling in W aldenström macroglobulinaemia cells
Author(s) -
Cao Yang,
Hunter Zachary R.,
Liu Xia,
Xu Lian,
Yang Guang,
Chen Jie,
Tsakmaklis Nickolas,
Kanan Sandra,
Castillo Jorge J.,
Treon Steven P.
Publication year - 2015
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.13200
Subject(s) - ibrutinib , mapk/erk pathway , cancer research , protein kinase b , biology , signal transduction , microbiology and biotechnology , chemistry , immunology , leukemia , chronic lymphocytic leukemia
Summary CXCR 4 WHIM frameshift and nonsense mutations follow MYD 88 L265P as the most common somatic variants in W aldenström M acroglobulinaemia ( WM ), and impact clinical presentation and ibrutinib response. While the nonsense ( CXCR 4 S338X ) mutation has been investigated, little is known about CXCR 4 frameshift ( CXCR 4 FS ) mutations. We engineered WM cells to express CXCR 4 FS mutations present in patients, and compared their CXCL 12 ( SDF ‐1a) induced signalling and ibrutinib sensitivity to CXCR 4 wild‐type (WT) and CXCR 4 S338X cells. Following CXCL 12 stimulation, CXCR 4 FS and CXCR 4 S338X WM cells showed impaired CXCR 4 receptor internalization, and enhanced AKT 1 (also termed AKT ) and MAPK 1 (also termed ERK ) activation versus CXCR WT cells ( P < 0·05), though MAPK 1 activation was more prolonged in CXCR 4 S338X cells ( P < 0·05). CXCR 4 FS and CXCR 4 S338X cells, but not CXCR 4 WT cells, were rescued from ibrutinib‐triggered apoptosis by CXCL 12 that was reversed by AKT 1, MAPK 1 or CXCR 4 antagonists. Treatment with an inhibitor that blocks MYD 88 L265P signalling triggered similar levels of apoptosis that was not abrogated by CXCL 12 treatment in CXCR 4 WT and CXCR 4 WHIM cells. These studies show a functional role for CXCR 4 FS mutations in WM , and provide a framework for the investigation of CXCR 4 antagonists with ibrutinib in CXCR 4 WHIM ‐mutated WM patients. Direct inhibition of MYD 88 L265P signalling overcomes CXCL 12 triggered survival effects in CXCR 4 WHIM ‐mutated cells supporting a primary role for this survival pathway in WM .