Real-world Safety and Effectiveness of 24-week Sofosbuvir and Ribavirin Treatment in Patients Infected with Rare Chronic Hepatitis C Virus Genotypes 3, 4, 5, or 6 in Japan.

Objectives Real-world evidence on the safety and effectiveness of direct-acting antivirals in patients infected with chronic hepatitis C virus (HCV) genotypes (GTs) 3, 4, 5, or 6 in Japan is limited. This prospective observational study assesses the real-world safety profile and treatment effectiveness among patients prescribed sofosbuvir with ribavirin (SOF+RBV) for HCV GT3-6 infection in Japan. Methods Adults receiving 24-week SOF+RBV treatment for HCV GT3-6 infection were prospectively enrolled and observed through 24 weeks post-treatment for treatment-emergent adverse events (AEs) considered related to SOF and/or RBV by treating physicians and for a sustained virologic response at 12 and 24 weeks post-treatment (SVR12, SVR24). Incidence rates of related AEs and serious AEs (SAEs) were calculated. Proportions of patients experiencing related AEs/SAEs and those achieving SVR12 and SVR24 were assessed overall and by baseline characteristics, including treatment experience and cirrhosis status. Results Among the 50 patients included in the safety analysis, 92% had GT3 infection. The incidence rates of related AEs and SAEs were low overall (1.52 and 0.25 per 100 person-weeks, respectively), with 6.0% and 14.0% patients experiencing AEs related to SOF or RBV, respectively. There were no marked differences in the occurrence of related AEs/SAEs by patient baseline characteristics. SVR12 and SVR24 were achieved in 83.7% (41/49) and 82.2% (37/45) of patients, respectively. Lower effectiveness was observed among treatment-experienced patients and patients with cirrhosis at baseline. Conclusion This study demonstrated that SOF+RBV treatment for HCV GT3-6 infection was safe, effective, and an important treatment option for this difficult-to-treat patient population in Japan.

Overexpression of sPRDM16 coupled with loss of p53 induces myeloid leukemias in mice.

Transgenic expression of the abnormal products of acute myeloid leukemia-associated (AML-associated) primary chromosomal translocations in hematopoietic stem/progenitor cells initiates leukemogenesis in mice, yet additional mutations are needed for leukemia development. We report here aberrant expression of PR domain containing 16 (PRDM16) in AML cells with either translocations of 1p36 or normal karyotype. These carried, respectively, relatively high prevalence of mutations in the TP53 tumor suppressor gene and in the nucleophosmin (NPM) gene, which regulates p53. Two protein isoforms are expressed from PRDM16, which differ in the presence or absence of the PR domain. Overexpression of the short isoform, sPRDM16, in mouse bone marrow induced AML with full penetrance, but only in the absence of p53. The mouse leukemias were characterized by multilineage cellular abnormalities and megakaryocyte dysplasia, a common feature of human AMLs with 1p36 translocations or NPM mutations. Overexpression of sPRDM16 increased the pool of HSCs in vivo, and in vitro blocked myeloid differentiation and prolonged progenitor life span. Loss of p53 augmented the effects of sPRDM16 on stem cell number and induced immortalization of progenitors. Thus, overexpression of sPRDM16 induces abnormal growth of stem cells and progenitors and cooperates with disruption of the p53 pathway in the induction of myeloid leukemia.

Delocalization and destabilization of the Arf tumor suppressor by the leukemia-associated NPM mutant.

One third of acute myeloid leukemias (AMLs) are characterized by the aberrant cytoplasmic localization of nucleophosmin (NPM) due to mutations within its putative nucleolar localization signal. NPM mutations are mutually exclusive with major AML-associated chromosome rearrangements and are frequently associated with a normal karyotype, suggesting that they are critical during leukemogenesis. The underlying molecular mechanisms are, however, unknown. NPM is a nucleocytoplasmic shuttling protein that has been implicated in several cellular processes, including ribosome biogenesis, centrosome duplication, cell cycle progression, and stress response. It has been recently shown that NPM is required for the stabilization and proper nucleolar localization of the tumor suppressor p19(Arf). We report here that the AML-associated NPM mutant localizes mainly in the cytoplasm due to an alteration of its nucleus-cytoplasmic shuttling equilibrium, forms a direct complex with p19(Arf), but is unable to protect it from degradation. Consequently, cells or leukemic blasts expressing the NPM mutant have low levels of cytoplasmic Arf. Furthermore, we show that expression of the NPM mutant reduces the ability of Arf to initiate a p53 response and to induce cell cycle arrest. Inactivation of p19(Arf), a key regulator of the p53-dependent cellular response to oncogene expression, might therefore contribute to leukemogenesis in AMLs with mutated NPM.

FUS/ERG gene fusions in Ewing's tumors.

Ewing's tumors are rare pediatric neoplasms that are characterized by specific chromosomal translocations and gene rearrangements. All of the fusion genes reported to date in Ewing's tumors juxtapose the EWS gene at 22q12 to an ETS-related gene, the most common of which are FLI1 at 11q24 and ERG at 21q22. We present here four cases of Ewing's tumor, which showed no evidence of a EWS gene rearrangement, but instead contained translocations involving 16p11 and 21q22. A rearrangement involving the same chromosome bands, t(16;21)(p11;q22), is found in rare cases of acute myeloid leukemia and fuses the FUS gene at 16p11 to the ERG gene at 21q22. In two of our Ewing's tumor cases, we were able to show at the sequence level that the translocation between chromosomes 16 and 21 similarly results in a FUS/ERG fusion. In one case, exons 1-5 and most of exon 6 of FUS were fused in-frame to exon 9 of ERG; in the other case, FUS exons 1-7 were fused in-frame to ERG exons 8-9. The functional fusion transcript is expected to be expressed from the der(21)t(16;21) derivative. In the two other t(16;21)-positive Ewing's cases, we performed bacterial artificial chromosome fluorescence in situ hybridization analysis on metaphases and interphase nuclei to demonstrate colocalization of bacterial artificial chromosomes containing FUS and ERG genes, also highly suggestive of fusion gene formation. These represent the first four cases where FUS, rather than EWS, is rearranged with an ETS-family transcription factor in Ewing's tumors. Our data provide additional evidence that the transactivation domains of the TET family of RNA-binding proteins (such as EWS and FUS) are interchangeable, and suggests a novel mechanism of oncogenesis in Ewing's tumors.