Caspase-resistant ROCK1 expression prolongs survival ofEµ-MycB cell lymphoma mice

Abstract

AbstractApoptosis is characterized by membrane blebbing and apoptotic body formation. Caspase cleavage of ROCK1 generates an active fragment that promotes actin-myosin mediated contraction and membrane blebbing during apoptosis. Expression of caspase-resistant non-cleavable ROCK1 (Rock1 NC) prolonged survival of mice that rapidly develop B cell lymphomas due toEµ-Myctransgene expression.Eµ-Myc; Rock1 NCmice had significantly fewer bone marrow cells relative toEµ-Mycmice expressing wild-type ROCK1 (Rock1 WT), which was associated with altered cell cycle profiles. Circulating macrophage numbers were lower inEµ-Myc; Rock1 NCmice, but there were higher levels of bone marrow macrophages, consistent with spontaneous cell death inEµ-Myc; Rock1 NCmice bone marrows being more inflammatory.Rock1 WTrecipient mice transplanted with pre-neoplasticEµ-Myc; Rock1 NCbone marrow cells survived longer than mice transplanted withEµ-Myc; Rock1 WTcells, indicating that the survival benefit was intrinsic to theEµ-Myc; Rock1 NCbone marrow cells. The results suggest that the apoptotic death ofEµ-Myc; Rock1 NCcells generates a proliferation-suppressive microenvironment in bone marrows that reduces cell numbers and prolongs B cell lymphoma mouse survival.