Search

Myelodysplastic syndromes (MDS) are a genetically complex and phenotypically diverse set of clonal hematologic neoplasms that occur with increasing frequency with age. MDS has long been associated with systemic inflammatory conditions and disordered inflammatory signaling is implicated in MDS pathogenesis. A rise in sterile inflammation occurs with ageing and the term "inflammaging" has been coined by to describe this phenomenon. This distinct form of sterile inflammation has an unknown role in in the pathogenesis of myeloid malignancies despite shared correlations with age and ageing-related diseases. More recent is a discovery that many cases of MDS arise from clonal hematopoiesis of indeterminate potential (CHIP), an age associated, asymptomatic pre-disease state. The interrelationship between ageing, inflammation and clonal CHIP is complex and likely bidirectional with causality between inflammaging and CHIP potentially instrumental to understanding MDS pathogenesis. Here we review the concept of inflammaging and MDS pathogenesis and explore their causal relationship by introducing a novel framing mechanism of "pre-clonal inflammaging" and "clonal inflammaging". We aim to harmonize research on ageing, inflammation and MDS pathogenesis by contextualizing the current understanding of inflammaging and the ageing hematopoietic system with what is known about the etiology of MDS via its progression from CHIP.

Purpose: Treatment options are limited beyond JAK inhibitors for patients with primary myelofibrosis (MF) or secondary MF. Preclinical studies have revealed that PI3Kδ inhibition cooperates with ruxolitinib, a JAK1/2 inhibitor, to reduce proliferation and induce apoptosis of JAK2V617F-mutant cell lines., Patients and Methods: In a phase I dose-escalation and -expansion study, we evaluated the safety and efficacy of a selective PI3Kδ inhibitor, umbralisib, in combination with ruxolitinib in patients with MF who had a suboptimal response or lost response to ruxolitinib. Enrolled subjects were required to be on a stable dose of ruxolitinib for ≥8 weeks and continue that MTD at study enrollment. The recommended dose of umbralisib in combination with ruxolitinib was determined using a modified 3+3 dose-escalation design. Safety, pharmacokinetics, and efficacy outcomes were evaluated, and spleen size was measured with a novel automated digital atlas., Results: Thirty-seven patients with MF (median age, 67 years) with prior exposure to ruxolitinib were enrolled. A total of 2 patients treated with 800 mg umbralisib experienced reversible grade 3 asymptomatic pancreatic enzyme elevation, but no dose-limiting toxicities were seen at lower umbralisib doses. Two patients (5%) achieved a durable complete response, and 12 patients (32%) met the International Working Group-Myeloproliferative Neoplasms Research and Treatment response criteria of clinical improvement. With a median follow-up of 50.3 months for censored patients, overall survival was greater than 70% after 3 years of follow-up., Conclusions: Adding umbralisib to ruxolitinib in patients was well tolerated and may resensitize patients with MF to ruxolitinib without unacceptable rates of adverse events seen with earlier generation PI3Kδ inhibitors. Randomized trials testing umbralisib in the treatment of MF should be pursued., (©2023 American Association for Cancer Research.)

Treatment for myelodysplastic syndromes (MDS) remains insufficient due to clonal heterogeneity and lack of effective clinical therapies. Dysregulation of apoptosis is observed across MDS subtypes regardless of mutations and represents an attractive therapeutic opportunity. Venetoclax (VEN), a selective inhibitor of anti-apoptotic protein B-cell lymphoma- 2 (BCL2), has yielded impressive responses in older patients with acute myeloid leukemia (AML) and high risk MDS. BCL2 family anti-apoptotic proteins BCL-XL and induced myeloid cell leukemia 1 (MCL1) are implicated in leukemia survival, and upregulation of MCL1 is seen in VEN-resistant AML and MDS. We determined in vitro sensitivity of MDS patient samples to selective inhibitors of BCL2, BCL-XL and MCL1. While VEN response positively correlated with MDS with excess blasts, all MDS subtypes responded to MCL1 inhibition. Treatment with combined VEN + MCL1 inhibtion was synergistic in all MDS subtypes without significant injury to normal hematopoiesis and reduced MDS engraftment in MISTRG6 mice, supporting the pursuit of clinical trials with combined BCL2 + MCL1 inhibition in MDS.

Chronic myelomonocytic leukemia (CMML) is a myelodysplastic syndrome/myeloproliferative neoplasm overlap syndrome characterized by monocytic proliferation in the presence of dysplastic bone marrow changes, inflammatory symptoms, and propensity for transformation to acute myeloid leukemia (AML), with a poor prognosis and limited treatment options. Unlike the α and β isoforms, the phosphatidylinositol-3-kinase (PI3K)-δ signaling protein is predominantly expressed by hematopoietic cells and therefore has garnered interest as a potential target for the treatment of lymphomas and leukemias. We revealed a pattern of increased PIK3CD:PIK3CA ratio in monocytic M5 AML patients and cell lines, and this ratio correlated with responsiveness to pharmacological PI3K-δ inhibition in vitro. Because CMML is a disease defined by monocytic clonal proliferation, we tested the PI3K-δ inhibitor umbralisib as a single agent and in combination with the JAK1/2 inhibitor ruxolitinib, in CMML. Our ex vivo experiments with primary CMML patient samples revealed synergistic inhibition of viability and clonogenicity with this combination. Phospho-specific flow cytometry revealed that dual inhibition had the unique ability to decrease STAT5, ERK, AKT, and S6 phosphorylation simultaneously, which offers a mechanistic hypothesis for the enhanced efficacy of the combination treatment. These preclinical data indicate promising activity by co-inhibition of PI3K-δ and JAK1/2 and support the use of ruxolitinib + umbralisib combination therapy in CMML under active clinical investigation., Competing Interests: Conflict of interest disclosure MRS receives research funding from Astex, Incyte, Millennium, and TG Therapeutics; serves on consultancy/advisory board/monitoring committees for AbbVie, Astex, BMS, Celgene, Geron, Karyopharm, Millennium, Ryvu, Sunesis, and TG Therapeutics; has equity in Karyopharm; and has patents and royalties with Boehringer-Ingelheim. The remaining authors have no competing financial interests., (Copyright © 2021. Published by Elsevier Inc.)

Competing Interests: Declaration of competing interest MV has no disclosures. MS receives research funding from Astex, Incyte, Takeda and TG Therapeutics; consults and serves as advisory for BMS, Celgene, Karyopharm, Ryvu, Sierra Oncology, Takeda, TG Therapeutics; and has equity in Karyopharm.

Primary dural marginal zone lymphomas (MZLs) are exceptionally rare, with fewer than 100 cases reported to date. While the association between hepatitis C virus (HCV) infection and lymphoma is well established, it is unclear if this association extends to all anatomic sites. Here we report a case of dural MZL in a 61-year-old woman with an HCV infection. To our knowledge, this is the first report of a dural MZL associated with an HCV infection in an immunocompetent patient and was successfully treated with radiotherapy and rituximab. As such, future cases of primary MZL found in the dura should prompt consideration of co-infection with microbials such as HCV and upfront treatment with anti-virals should be considered., Competing Interests: None to declare., (Copyright 2020, Villaume et al.)

The selective inhibitor of nuclear export (SINE) compounds selinexor (KPT-330) and eltanexor (KPT-8602) are from a novel class of small molecules that target exportin-1 (XPO1 [CRM1]), an essential nucleo-cytoplasmic transport protein responsible for the nuclear export of major tumor suppressor proteins and growth regulators such as p53, p21, and p27. XPO1 also affects the translation of messenger RNAs for critical oncogenes, including MYC, BCL2, MCL1, and BCL6, by blocking the export of the translation initiation factor eIF4E. Early trials with venetoclax (ABT-199), a potent, selective inhibitor of BCL2, have revealed responses across a variety of hematologic malignancies. However, many tumors are not responsive to venetoclax. We used models of acute myeloid leukemia (AML) and diffuse large B-cell lymphoma (DLBCL) to determine in vitro and in vivo responses to treatment with venetoclax and SINE compounds combined. Cotreatment with venetoclax and SINE compounds demonstrated loss of viability in multiple cell lines. Further in vitro analyses showed that this enhanced cell death was the result of an increase in apoptosis that led to a loss of clonogenicity in methylcellulose assays, coinciding with activation of p53 and loss of MCL1. Treatment with SINE compounds and venetoclax combined led to a reduction in tumor growth in both AML and DLBCL xenografts. Immunohistochemical analysis of tissue sections revealed that the reduction in tumor cells was partly the result of an induction of apoptosis. The enhanced effects of this combination were validated in primary AML and DLBCL patient cells. Our studies reveal synergy with SINE compounds and venetoclax in aggressive hematologic malignancies and provide a rationale for pursuing this approach in a clinical trial., (© 2020 by The American Society of Hematology.)

The fungal-derived Taiwanese natural product antroquinonol A has attracted both academic and commercial interest due to its reported exciting biological properties. This reduced quinone is currently in phase II trials (USA and Taiwan) for the treatment of non-small-cell lung carcinoma (NSCLC) and was recently granted orphan drug status by the FDA for the treatment of pancreatic cancer and acute myeloid leukemia. Pending successful completion of human clinical trials, antroquinonol is expected to be commercialized under the trade name Hocena. A synthesis-enabled biological re-examination of this promising natural product, however, reveals minimal in vitro and in vivo antitumor activity in preclinical models.

The polycycles merochlorin A and B are complex halogenated meroterpenoid natural products with significant antibacterial activities and are produced by the marine bacterium Streptomyces sp. strain CNH-189. Heterologously produced enzymes and chemical synthesis are employed herein to fully reconstitute the merochlorin biosynthesis in vitro. The interplay of a dedicated type III polyketide synthase, a prenyl diphosphate synthase, and an aromatic prenyltransferase allow formation of a highly unusual aromatic polyketide-terpene hybrid intermediate which features an unprecedented branched sesquiterpene moiety from isosesquilavandulyl diphosphate. As supported by in vivo experiments, this precursor is furthermore chlorinated and cyclized to merochlorin A and isomeric merochlorin B by a single vanadium-dependent haloperoxidase, thus completing the remarkably efficient pathway., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)