CRM1 inhibition induces tumor cell cytotoxicity and impairs osteoclastogenesis in multiple myeloma: molecular mechanisms and therapeutic implications.

The key nuclear export protein CRM1/XPO1 may represent a promising novel therapeutic target in human multiple myeloma (MM). Here we showed that chromosome region maintenance 1 (CRM1) is highly expressed in patients with MM, plasma cell leukemia cells and increased in patient cells resistant to bortezomib treatment. CRM1 expression also correlates with increased lytic bone and shorter survival. Importantly, CRM1 knockdown inhibits MM cell viability. Novel, oral, irreversible selective inhibitors of nuclear export (SINEs) targeting CRM1 (KPT-185, KPT-330) induce cytotoxicity against MM cells (ED50<200 nM), alone and cocultured with bone marrow stromal cells (BMSCs) or osteoclasts (OC). SINEs trigger nuclear accumulation of multiple CRM1 cargo tumor suppressor proteins followed by growth arrest and apoptosis in MM cells. They further block c-myc, Mcl-1, and nuclear factor κB (NF-κB) activity. SINEs induce proteasome-dependent CRM1 protein degradation; concurrently, they upregulate CRM1, p53-targeted, apoptosis-related, anti-inflammatory and stress-related gene transcripts in MM cells. In SCID mice with diffuse human MM bone lesions, SINEs show strong anti-MM activity, inhibit MM-induced bone lysis and prolong survival. Moreover, SINEs directly impair osteoclastogenesis and bone resorption via blockade of RANKL-induced NF-κB and NFATc1, with minimal impact on osteoblasts and BMSCs. These results support clinical development of SINE CRM1 antagonists to improve patient outcome in MM.

Use of repeated matings to estimate environmental and genetic trends and effects of relaxing selection in a selected strain of Leghorn chickens.

Response from index selection for egg production traits in a Leghorn strain over 7 years was partitioned into estimates of total (delta T), temporary (delta R), and net genetic (delta G) response, by producing progeny from selected (A) and unselected (D) first year breeders and from second year breeders (B) and first year full-sisters of previous years A breeders (C). In A, B, C, and D populations, average yearly number of full-sib families was 121, 47, 37, and about 50 and of birds with complete records was 824, 287, 258, and 298. Restricting A to repeated B families added positive bias in delta G for viability, age at first egg, and rate of lay. Estimates of delta G and delta R from B and C populations were similar. Yearly environmental change (delta E) was over three times the phenotypic change (delta P) for egg numbers, emphasizing necessity for intra-year estimates of delta G and delta R. Temporary response (delta R) approached or exceeded total response (delta T) for mortality and accounted for 40% of delta T for rate of lay and 60% for economic index, suggesting adverse maternal environmental effects from relaxing selection (D). Net yearly genetic change (delta G) was 1.5% for rate of lay, $.18 per bird, and in desired direction for most traits. Estimated net yearly response for rate of lay exceeded that predicted from .64 sigma male and .92 sigma female index selection differentials and sire-component genetic parameters (.6%) but agreed ($.16) for economic index. Efficiency and bias for the repeat-mating design are handicapped by mortality and health-related maternal effects.