Search

Background: Osteoarthritis (OA) is a progressive degenerative disease with an inflammatory background. Chronic myeloproliferative neoplasms (MPN) are clonal hematopoietic disorders characterized by chronic inflammation and a tendency for connective tissue remodeling. Aim: This study aimed to investigate the prevalence and associated risk factors of symptomatic OA (sOA) in MPN patients. Patients and methods: A total of 100 consecutive MPN (39 essential-thrombocythemia, 34 polycythemia-vera, 27 myelofibrosis) patients treated in two community hematologic centers were cross-sectionally evaluated. Patients were required to have both symptoms attributable to hip and/or knee OA and radiographic confirmation to be considered as having sOA. Results: The prevalence of hip and/or knee sOA was significantly higher among MPN patients than the previously reported prevalence in the general population of similar age (61% vs. 22%, p < 0.001). Hip sOA was present in 50%, knee sOA in 51% and sOA of both localizations in 41% of patients. A high proportion of MPN patients had radiographic signs of hip OA (94%) and knee OA (98%) in the presence of attributable symptoms. Among the other factors, sOA was univariately associated with the presence of JAK2 mutation, myelofibrosis phenotype, older age, higher body weight, and higher MPN-SAF score (p < 0.050 for all analyses). In the multivariate analysis, older age (odds ratio = 1.19, 95% confidence interval-CI 1.06–1.33) and higher body weight (OR = 1.15, 95% CI 1.06–1.25) were recognized as independent risk factors for sOA. On the other hand, cytoreductive treatment was a protective factor for sOA (OR = 0.07, 95% CI 0.006–0.86). Conclusions: The prevalence of sOA in MPN patients was higher than that in the general population and seems to correlate with older age, increased myeloproliferation and a higher inflammatory state. Whether cytoreductive treatment may postpone OA development in MPN patients warrants additional confirmation. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is a complex disease with an aggressive clinical course and high mortality rate. The standard of care for patients has only changed minimally over the past 40 years. However, potentially useful agents have moved from bench to bedside with the potential to revolutionize therapeutic strategies. As such, cell-cycle inhibitors have been discussed as alternative treatment options for AML. In this review, we focus on cyclin-dependent kinase 6 (CDK6) emerging as a key molecule with distinct functions in different subsets of AML. CDK6 exerts its effects in a kinase-dependent and -independent manner which is of clinical significance as current inhibitors only target the enzymatic activity. [ABSTRACT FROM AUTHOR]

JAK2-V617F plays a key role in the pathogenesis of myeloproliferative neoplasm. However, its inhibitor ruxolitinib has shown limited clinical efficacies because of the ruxolitinib-persistent proliferation of JAK2-V617F-positive cells. We here demonstrate that the USP9X inhibitor WP1130 or EOAI3402143 (G9) inhibited proliferation and induced apoptosis more efficiently in cells dependent on JAK2-V617F than on cytokine-activated JAK2. WP1130 preferentially downregulated activated and autophosphorylated JAK2-V617F by enhancing its K63-linked polyubiquitination and inducing its aggresomal translocation to block downstream signaling. Furthermore, JAK2-V617F associated physically with USP9X in leukemic HEL cells. Induction of apoptosis by inhibition of USP9X was mediated through the intrinsic mitochondria-mediated pathway, synergistically enhanced by BH3 mimetics, prevented by overexpression of Bcl-xL, and required oxidative stress to activate stress-related MAP kinases p38 and JNK as well as DNA damage responses in HEL cells. Although autophosphorylated JAK2-V617F was resistant to WP1130 in the ruxolitinib-persistent HEL-R cells, these cells expressed Bcl-2 and Bcl-xL at lower levels and showed an increased sensitivity to WP1130 as well as BH3 mimetics as compared with ruxolitinib-naive HEL cells. Thus, USP9X represents a promising target along with anti-apoptotic Bcl-2 family members for novel therapeutic strategies against JAK2-V617F-positive myeloproliferative neoplasms, particularly under the ruxolitinib persistence conditions. [ABSTRACT FROM AUTHOR]