Caspase-resistant ROCK1 expression prolongs survival of E-mu-Myc B cell lymphoma mice.

Abstract

Apoptosis 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 to E{micro}-Myc transgene expression. E{micro}-Myc; Rock1 NC mice had significantly fewer bone marrow cells relative to E{micro}-Myc mice expressing wild-type ROCK1 (Rock1 WT), which was associated with altered cell cycle profiles. Circulating macrophage numbers were lower in E{micro}-Myc; Rock1 NC mice, but there were higher levels of bone marrow macrophages, consistent with spontaneous cell death in E{micro}-Myc; Rock1 NC mice bone marrows being more inflammatory. Rock1 WT recipient mice transplanted with pre-neoplastic E{micro}-Myc; Rock1 NC bone marrow cells survived longer than mice transplanted with E{micro}-Myc; Rock1 WT cells, indicating that the survival benefit was intrinsic to the E{micro}-Myc; Rock1 NC bone marrow cells. The results suggest that the apoptotic death of E{micro}-Myc; Rock1 NC cells generates a proliferation-suppressive microenvironment in bone marrows that reduces cell numbers and prolongs B cell lymphoma mouse survival.