Ten years after ruxolitinib approval for myelofibrosis: a review of clinical efficacy

Leukemia & lymphoma/Leukemia and lymphoma · 2023 · 44 citations

• Medicine
• Internal medicine
• Oncology

Myelofibrosis (MF) is a chronic myeloproliferative neoplasm characterized by splenomegaly, abnormal cytokine expression, cytopenias, and progressive bone marrow fibrosis. The disease often manifests with burdensome symptoms and is associated with reduced survival. Ruxolitinib, an oral Janus kinase (JAK) 1 and JAK2 inhibitor, was the first agent approved for MF. As a first-in-class targeted treatment, ruxolitinib approval transformed the MF treatment approach and remains standard of care. In addition, targeted inhibition of JAK1/JAK2 signaling, a key molecular pathway underlying MF pathogenesis, and the large volume of literature evaluating ruxolitinib, have led to a better understanding of the disease and improved management in general. Here we review ruxolitinib efficacy in patients with MF in the 10 years following approval, including demonstration of clinical benefit in the phase 3 COMFORT-I/II trials, real-world evidence, translational studies, and expanded access data. Lastly, future directions for MF treatment are discussed, including ruxolitinib-based combination therapies.

Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis (MOMENTUM): results from an international, double-blind, randomised, controlled, phase 3 study

The Lancet · 2023 · 177 citations

• Medicine
• Internal medicine
• Gastroenterology

Cigarette Smoke and E-Cigarette Aerosols Lead to Clonal Expansion of Tet2 -/- and Dnmt3a R878H Cells In Vivo

Blood · 2021 · 1 citations

• Biology
• Immunology
• Cancer research

Abstract Background: Environmental factors must play a significant role in the emergence of clonal hematopoiesis since only a fraction of individuals harboring clonal hematopoiesis of indeterminate potential (CHIP) mutations develop hematologic malignancy. Mouse models of chronic inflammation have demonstrated clonal expansion of Tet2 and Dnmt3a knockout hematopoietic cells while Ppm1d mutated clones exhibit clonal dominance in response to cytotoxic DNA damaging chemotherapy stress. Epidemiologic studies have associated smoking behavior with clonal hematopoiesis but the leukemogenic effects of cigarette smoke on hematopoietic stem cells (HSCs) are poorly defined. In addition, the exploding use of electronic (e)-cigarettes has led to significant concern on their detrimental health effects plus studies of E-cigarettes on the hematopoietic system are non-existent. Here, we investigated the role of cigarette smoke and E-cigarette aerosols in promoting clonal expansion of common CHIP mutations. We hypothesize that one or more specific somatic CHIP mutation displays a fitness advantage in the presence of cigarette smoke and/or e-cigarette aerosols. Methods: Competitive bone marrow transplant assays were used to determine the development of clonal expansion in response to cigarette smoke and E-cigarette aerosols using Tet2 knockout (Tet2 -/-), Dnmt3a R878H and Jak2 V617F genetically modified mice. Lethally irradiated recipient mice in the CD45.1/2 background were transplanted with whole bone marrow cells from wild type (WT) (CD45.1) and mutant (CD45.2) mice. Ratio of cells transplanted were 1:10 for Tet2 -/- and WT; 1:5 for Dnmt3a R878H and WT and 1:1 for Jak2 V617F and WT. Transplanted mice were exposed to cigarette smoke or E-cigarette aerosols using a nose-only inhalation exposures system for 2 hours/day, 4 days/week for 2 or 3 months. Control mice were exposed to room air using the nose-only inhalation approach. Results: After 2 months of exposure, we observed that Tet2 -/- cells had significantly expanded in the smoke group (paired t-test, p<0.05) while there was no significant difference in the air group (Fig. 1A). Furthermore, this increase in Tet2 -/- cells was more pronounced in the myeloid cell subset (Fig. 1B). While the knock-in mouse model of Jak2 V617F does not display a competitive advantage in a lethally irradiated bone marrow transplant setting, we observed persisting levels of Jak2 V617F mutant cells following smoke exposure but significantly reduced levels in the air group, illustrating that the mutant cells prevail in a smoke environment (Fig. 1C). During sacrifice of the Jak2 V617F transplanted and exposed mice, long-term HSCs in the bone marrow exhibited a trend towards increased bromodeoxyuridine (BrdU) incorporation and increased DNA damage as determined by H2AX staining (Fig 1D). Meanwhile, E-cigarette aerosol exposure of mice transplanted with Dnmt3a R878H cells, displayed increased levels of circulating mutant cells compared to the air group (Fig. 1E) (repeated measures, 2-way ANOVA). Conclusion: In vivo exposure of mouse models of CHIP to cigarette smoke and E-cigarette aerosols promotes mutant cell expansion over time. Our data indicate that more than one mutation is selected by environmental factors in the form of tobacco products. This data is important to guide us in preventive medicine and early detection of clonal hematopoiesis. Future research is aimed at deciphering the molecular responses of WT cells to cigarette smoke and E-cigarette aerosols and strategies to preserve WT stem cell fitness in the context of smoking and E-cigarette usage. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Drug‐like sphingolipid SH‐BC‐893 opposes ceramide‐induced mitochondrial fission and corrects diet‐induced obesity

EMBO Molecular Medicine · 2021 · 28 citations

• Biology
• Cell biology
• Endocrinology

Ceramide-induced mitochondrial fission drives high-fat diet (HFD)-induced obesity. However, molecules targeting mitochondrial dynamics have shown limited benefits in murine obesity models. Here, we reveal that these compounds are either unable to block ceramide-induced mitochondrial fission or require extended incubation periods to be effective. In contrast, targeting endolysosomal trafficking events important for mitochondrial fission rapidly and robustly prevented ceramide-induced disruptions in mitochondrial form and function. By simultaneously inhibiting ARF6- and PIKfyve-dependent trafficking events, the synthetic sphingolipid SH-BC-893 blocked palmitate- and ceramide-induced mitochondrial fission, preserved mitochondrial function, and prevented ER stress in vitro. Similar benefits were observed in the tissues of HFD-fed mice. Within 4 h of oral administration, SH-BC-893 normalized mitochondrial morphology in the livers and brains of HFD-fed mice, improved mitochondrial function in white adipose tissue, and corrected aberrant plasma leptin and adiponectin levels. As an interventional agent, SH-BC-893 restored normal body weight, glucose disposal, and hepatic lipid levels in mice consuming a HFD. In sum, the sphingolipid analog SH-BC-893 robustly and acutely blocks ceramide-induced mitochondrial dysfunction, correcting diet-induced obesity and its metabolic sequelae.