Carfilzomib plus dexamethasone in patients with relapsed and refractory multiple myeloma: A retro-prospective observational study

Objective: We investigate safety and efficacy in common clinical practice of the combination of carfilzomib and dexamethasone (Kd56) approved for the ENDEAVOR trial for the treatment of relapsed or refractory multiple myeloma. Methods: We retro-prospective analyzed 75 patients in three centers in Tuscany, 48 of whom had a clinically relevant comorbidity and 50 of whom were older than 65 years, treated with a median use in the fourth line of therapy. We assessed the efficacy based on the International Myeloma Working Group criteria. Results: The overall response rate was 60%. Median PFS was 10 months in the general cohort; in patients treated for more than 1 cycle of therapy PFS was 12 months. Quality of response to Kd56 treatment was found to positively impact PFS. Refractory status to previous line of therapy or to lenalidomide or an history of exposure to pomalidomide, seemed to have no impact on survival. We also showed a low adverse events rate, with no neuropathy events, and a relatively small number of cardiovascular events above grade 3 (10%). Conclusion: Kd56 is an effective and well tolerated regimen in highly pretreated and elderly patients with a good safety profile

Extraordinary Molecular Evolution in the PRDM9 Fertility Gene

Recent work indicates that allelic incompatibility in the mouse PRDM9 (Meisetz) gene can cause hybrid male sterility, contributing to genetic isolation and potentially speciation. The only phenotype of mouse PRDM9 knockouts is a meiosis I block that causes sterility in both sexes. The PRDM9 gene encodes a protein with histone H3(K4) trimethyltransferase activity, a KRAB domain, and a DNA-binding domain consisting of multiple tandem C2H2 zinc finger (ZF) domains. We have analyzed human coding polymorphism and interspecies evolutionary changes in the PRDM9 gene. The ZF domains of PRDM9 are evolving very rapidly, with compelling evidence of positive selection in primates. Positively selected amino acids are predominantly those known to make nucleotide specific contacts in C2H2 zinc fingers. These results suggest that PRDM9 is subject to recurrent selection to change DNA-binding specificity. The human PRDM9 protein is highly polymorphic in its ZF domains and nearly all polymorphisms affect the same nucleotide contact residues that are subject to positive selection. ZF domain nucleotide sequences are strongly homogenized within species, indicating that interfinger recombination contributes to their evolution. PRDM9 has previously been assumed to be a transcription factor required to induce meiosis specific genes, a role that is inconsistent with its molecular evolution. We suggest instead that PRDM9 is involved in some aspect of centromere segregation conflict and that rapidly evolving centromeric DNA drives changes in PRDM9 DNA-binding domains

Transformation induced by Ewing's sarcoma associated EWS/FLI-1 is suppressed by KRAB/FLI-1

Ewing's sarcoma is a childhood bone tumour with poor prognosis, most commonly associated with a t(11;22)(q24;q12) reciprocal translocation that fuses the EWS and FLI-1 genes, resulting in the production of an aberrant chimeric transcription factor EWS/FLI-1. To erucidate the mechanisms by which EWS/FLI-1 mediates transformation in mouse models, we have generated a murine Ews/Fli-1 fusion protein. We demonstrate that this protein transforms fibroblast celrs in vitro similar to human EWS/FLI-1 as demonstrated by serum and anchorage-independent growth, the formation of tumours in nude mice and elevation of the oncogenic marker c-myc. Furthermore, transformation of these cells was inhibited by a specific represser, KRAB/FLI-1. The KRAB/FLI-1 repressor also suppressed the tumorigenic phenotype of a human Ewing's sarcoma cell line. These findings suggest that the transformed phenotype of Ewing's sarcoma cells can be reversed by using the sequence-specific FLI-1-DNA-binding domain to target a gone repressor domain. The inhibition of EWS/FLI-1 is the first demonstration of the KRAB domain suppressing the action of an ETS factor. This approach provides potential avenues for the elucidation of the biological mechanisms of EWS/FLI-1 oncogenesis and the development of novel therapeutic strategies. © 2003 Cancer Research UK.link_to_subscribed_fulltex

Transcriptional silencing of human immunodeficiency virus type 1 long terminal repeat-driven gene expression by the Kr\ufcppel-associated box repressor domain targeted to the transactivating response element.

The evolutionarily conserved protein domain, called the Kr\ufcppel-associated box (KRAB), present in the amino termini of a large number of Kr\ufcppel-type zinc finger proteins is a strong repressor domain. In order to develop novel strategies to control human immunodeficiency virus type 1 (HIV-1) gene expression, we constructed a series of expression vectors expressing the wild-type Tat or Tat transdominant negative mutants fused to the KRAB repressor domain. We found that the KRAB domain tethered to the transactivating response element is able to suppress both basal and Tat-mediated activity of HIV-1 long terminal repeat-driven gene expression. These results suggest that the KRAB repressor domain fused to the Tat transdominant negative mutants can be successfully employed to control HIV-1 gene expression

Transcriptional silencing of human immunodeficiency virus type 1 long terminal repeat-driven gene expression by the Kruppel-associated box repressor domain targeted to the transactivating response element

The evolutionarily conserved protein domain, called the Kruppel- associated box (KRAB), present in the amino termini of a large number of Kruppel-type zinc finger proteins is a strong repressor domain. In order to develop novel strategies to control human immunodeficiency virus type 1 (HIV- 1) gene expression, we constructed a series of expression vectors expressing the wild-type Tat or Tat transdominant negative mutants fused to the KRAB repressor domain. We found that the KRAB domain tethered to the transactivating response element is able to suppress both basal and Tat- mediated activity of HIV-1 lung terminal repeat-driven gene expression. These results suggest that the KRAB repressor domain fused to the Tat transdominant negative mutants can be successfully employed to control HIV-1 gene expression