Functional association of NR4A3 downregulation with impaired differentiation in myeloid leukemogenesis.

The coincident downregulation of NR4A1 and NR4A3 has been implicated in myeloid leukemogenesis, but it remains unknown how these two genes function in myeloid cells and how their combined downregulation promotes myeloid leukemogenesis. Since NR4A1 abrogation is thought to confer a survival and proliferation advantage to myeloid cells, we hypothesized that downregulation of NR4A3 may have a complementary effect on myeloid cell differentiation. First, we tested the association between differentiation status of leukemic cells and NR4A3 expression using two large clinical datasets from patients with different acute myeloid leukemia (AML) subtypes. The analysis revealed a close association between differentiation status and different subtypes of AML Then, we probed the effects of differentiation-inducing treatments on NR4A3 expression and NR4A3 knockdown on cell differentiation using two myeloid leukemia cell lines. Differentiation-inducing treatments caused upregulation of NR4A3, while NR4A3 knockdown prevented differentiation in both cell lines. The cell culture findings were validated using samples from chronic myeloid leukemia (CML) patients at chronic, accelerated and blastic phases, and in acute promyelocytic leukemia (APL) patients before and after all trans-retinoic acid (ATRA)-based differentiation therapy. Progressive NR4A3 downregulation was coincident with impairments in differentiation in patients during progression to blastic phase of CML, and NR4A3 expression was increased in APL patients treated with ATRA-based differentiating therapy. Together, our findings demonstrate a tight association between impaired differentiation status and NR4A3 downregulation in myeloid leukemias, providing a plausible mechanistic explanation of how myeloid leukemogenesis might occur upon concurrent downregulation of NR4A1 and NR4A3.

Hepatitis B Surface Antigen Positivity Is an Independent Unfavorable Prognostic Factor in Diffuse Large B-Cell Lymphoma in the Rituximab Era.

BACKGROUND: Patients with diffuse large B-cell lymphoma (DLBCL) with concurrent hepatitis B surface antigen (HBsAg)-positive hepatitis B virus (HBV) infection have distinct clinical features. Nevertheless, the prognostic value of HBsAg in DLBCL in the rituximab era remains unclear. MATERIALS AND METHODS: We conducted a retrospective cohort study to investigate the clinical relevance of HBsAg in immunocompetent patients with DLBCL treated with homogeneous rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone between 2002 and 2016. RESULTS: Among 416 analyzed patients, 98 (23.6%) were HBsAg positive. HBsAg positivity was associated with a younger age and more advanced stage at diagnosis, more frequent hepatic impairment during perichemotherapy, and a trend of higher National Comprehensive Cancer Network-International Prognostic Index (NCCN-IPI) score at diagnosis. Compared with the HBsAg-negative patients, the HBsAg-positive patients had a lower overall response rate (76.5% vs. 85.5%, p = .043), poorer 5-year overall survival (OS) rate (57.2% vs. 73.5%, p < .001), and shorter 5-year progression-free survival (PFS) rate (47.2% vs. 60.7%, p = .013). Multivariate analyses showed that HBsAg positivity was an independent unfavorable prognostic indicator for OS and PFS. A scoring system incorporating HBsAg positivity, the NCCN-IPI score, and serum albumin levels proved to be useful for stratifying prognostically relevant subgroups of patients with DLBCL. CONCLUSION: This study demonstrated that HBV infection is uniquely relevant to DLBCL. HBsAg might serve as a novel biomarker to improve clinical risk stratification of patients with DLBCL in areas with high prevalence of HBV infection. Further research investigating the etiopathogenesis of HBV infection in DLBCL is imperative. IMPLICATIONS FOR PRACTICE: A considerable disparity exists regarding the prognostic relevance of hepatitis B surface antigen (HBsAg)-positive hepatitis B virus (HBV) infection in patients with diffuse large B-cell lymphoma (DLBCL). In this large, retrospective cohort study from an area with high prevalence of HBV infection, the authors demonstrated that HBsAg was an independent unfavorable factor significantly associated with survival, highlighting its potential as a novel prognostic indicator to improve the risk stratification of patients with DLBCL in the rituximab era.

Guidelines for treating iron overload in myelodysplastic syndromes: a Taiwan consensus statement.

Iron overload is common in myelodysplastic syndrome (MDS) patients, and an accumulation of evidence shows that iron chelation may have benefits in these patients. However, discussion and consensus about iron chelation therapy (ICT) for MDS patients is lacking in Taiwan and other Southeast Asian countries. An Expert Panel in Taiwan was organized in 2011 to develop iron overload guidelines and provide a uniform reference for physicians treating MDS patients with iron overload, with specific regard to when to initiate ICT, in which patients, and the clinical and scientific rationale behind its use.