Background: Bortezomib, lenalidomide, and dexamethasone (VRd) is a standard therapy for newly diagnosed multiple myeloma (NDMM). Carfilzomib, a next-generation proteasome inhibitor, in combination with lenalidomide, and dexamethasone (KRd) has shown excellent efficacy in phase II trials and may improve outcomes compared with VRd.

• SL-401 was well tolerated, and a single course of treatment produced a high rate of objective responses in BPDCN patients.This is the first prospective study of treatment of patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), an aggressive hematologic malignancy derived from plasmacytoid dendritic cells that typically involves the skin and rapidly progresses to a leukemia phase. Despite being initially responsive to intensive combination chemotherapy, most patients relapse and succumb to their disease. Because BPDCN blasts overexpress the interleukin-3 receptor (IL3R), the activity of SL-401, diptheria toxin (DT) 388 IL3 composed of the catalytic and translocation domains of DT fused to IL3, was evaluated in BPDCN patients in a phase 1-2 study. Eleven patients were treated with a single course of SL-401 at 12.5 mg/kg intravenously over 15 minutes daily for up to 5 doses; 3 patients who had initial responses to SL-401 received a second course in relapse. The most common adverse events including fever, chills, hypotension, edema, hypoalbuminemia, thrombocytopenia, and transaminasemia were transient. Seven of 9 evaluable (78%) BPDCN patients had major responses including 5 complete responses and 2 partial responses after a single course of SL-401. The median duration of responses was 5 months (range, 1-201 months). Further studies of SL-401 in BPDCN including those involving multiple sequential courses, alternate schedules, and combinations with other therapeutics are warranted. This trial is registered at clinicaltrials.gov as #NCT00397579. (Blood. 2014;124(3):385-392)

Neuroblastoma (NB) is a common childhood malignant tumor of the neural crest-derived sympathetic nervous system. In NB the frequent loss of heterozygosity (LOH) on chromosome 1p raises the possibility that this region contains tumor-suppressor genes whose inactivation contributes to tumorigenesis. The human homolog of the Drosophila neural fate determination gene CASZ1, a zinc-finger transcription factor, maps to chromosome 1p36.22, a region implicated in NB tumorigenesis. Quantitative real-time PCR analysis showed that low-CASZ1 expression is significantly correlated with increased age (Z18 months), Children's Oncology Group high-risk classification, 1p LOH and MYCN amplification (all Po0.0002) and decreased survival probability (P ¼ 0.0009). CASZ1 was more highly expressed in NB with a differentiated histopathology (Po0.0001). Retinoids and epigenetic modification agents associated with regulation of differentiation induced CASZ1 expression. Expression profiling analysis revealed that CASZ1 regulates the expression of genes involved in regulation of cell growth and developmental processes. Specific restoration of CASZ1 in NB cells induced cell differentiation, enhanced cell adhesion, inhibited migration and suppressed tumorigenicity. These data are consistent with CASZ1 being a critical modulator of neural cell development, and that somatically acquired disruption of normal CASZ1 expression contributes to the malignant phenotype of human NB.

Castor is a zinc finger transcription factor that controls cell fate within neuroblast cell lineages in Drosophila melanogaster. Here, we describe the cloning and characterization of a human castor gene (CASZ1) that is structurally homologous to Drosophila castor. We find the expression of castor gene is increased when cells of neural origin as well as mesenchymal origin are induced to differentiation. CASZ1 is expressed in a number of normal tissues and exists in at least two mRNA species of 4.4 and 8.0kb. They are named hCasz5 and hCasz11 because the predicted proteins have 5 and 11 zinc fingers, respectively. Deletion analysis of the proximal 5'-flanking sequences delineates sequences sufficient to drive transcription in cells of neural and non-neural origin. Both hCasz5 and hCasz11 localize predominantly in the nucleus, consistent with their role as Zn-finger containing transcription factor. CASZ1 is expressed in a number of human tumors and localizes to a chromosomal region frequently lost in tumors of neuroectodermal origin.