Introduction: The abnormally activated JAK-STAT pathway plays a central role in the pathogenesis of BCR/ABL-negative myeloproliferative neoplasms (MPNs), simultaneously providing a theoretical and clinical basis for the development of small-molecule compounds targeting JAK. The first approved drug, ruxolitinib, demonstrated a rapid and durable improvement of symptoms and splenomegaly accompanied with better overall survival in myelofibrosis (MF) patients. However, ruxolitinib-related adverse effects and resistance are limitations, so there is an urgent need to develop new JAK inhibitors to retain the efficacy of ruxolitinib and avoid its deficiency. Areas covered: This review discusses the preclinical and clinical studies of momelotinib (MMB) aiming to gain a deeper understanding of the advantages and clinical limitations of this drug. Expert opinion: The clinical trial data available thus far indicate that MMB is not inferior to ruxolitinib in spleen response and symptoms response, with the improvement of anemia surprising. The only obstacle that may slowdown its approval is treatment-emerged peripheral neuropathy (PN). If we can minimize MMB’s treatment-related PN by administration optimization, MMB promises to be a good choice of individualized treatment for MF patients mainly manifesting as anemia.

Purpose. Poly(ADP-ribose) polymerase 1 (PARP1) is necessary for single-strand break (SSB) repair by sensing DNA breaks and facilitating DNA repair through poly ADP-ribosylation of several DNA-binding and repair proteins. Inhibition of PARP1 results in collapsed DNA replication fork and double-strand breaks (DSBs). Accumulation of DSBs goes beyond the capacity of DNA repair response, ultimately resulting in cell death. This work is aimed at assessing the synergistic effects of the DNA-damaging agent temozolomide (TMZ) and the PARP inhibitor niraparib (Nira) in human multiple myeloma (MM) cells. Materials and Methods. MM RPMI8226 and NCI-H929 cells were administered TMZ and/or Nira for 48 hours. CCK-8 was utilized for cell viability assessment. Cell proliferation and apoptosis were detected flow-cytometrically. Immunofluorescence was performed for detecting γH2A.X expression. Soft-agar colony formation assay was applied to evaluate the antiproliferative effect. The amounts of related proteins were obtained by immunoblot. The combination index was calculated with the CompuSyn software. A human plasmacytoma xenograft model was established to assess the anti-MM effects in vivo. The anti-MM activities of TMZ and/or Nira were evaluated by HE staining, IHC, and the TUNEL assay. Results. The results demonstrated that cotreatment with TMZ and Nira promoted DNA damage, cell cycle arrest, and apoptotic death in cultured cells but also reduced MM xenograft growth in nude mice, yielding highly synergistic effects. Immunoblot revealed that TMZ and Nira cotreatment markedly increased the expression of p-ATM, p-CHK2, RAD51, and γH2A.X, indicating the suppression of DNA damage response (DDR) and elevated DSB accumulation. Conclusion. Inhibition of PARP1 sensitizes genotoxic agents and represents an important therapeutic approach for MM. These findings provide preliminary evidence for combining PARP1 inhibitors with TMZ for MM treatment.

The predominance of ageing in patients with multiple myeloma (MM) results in at least 30% of patients being classified as frail at diagnosis. Compared with

Acute myeloid leukemia (AML) is an aggressive clonal malignancy of hematopoietic progenitors with poor clinical outcomes. Though many patients respond well to induction chemotherapy, relapse occurs. The mechanisms underlying AML chemoresistance remain unclear. In our study, we performed whole transcriptome sequencing (WTS) on diagnosed AML samples sensitive or resistant to IA (idarubicin and cytarabine) induction treatment. We observed that lncRNA AC021683.2 is upregulated in IA-resistant patients and associated with poor prognosis. AC021683.2 depletion increased the chemosensitivity of AML cells to Ara-C both in vitro and in vivo by accelerating BCLAF1 ubiquitination and degradation, and AC021683.2 depletion enhanced sensitivity partially by depending on BCLAF1. Both AC021683.2 and BCLAF1 positively correlated with RAD50, which mediated their roles in Ara-C-resistant AML cells. These findings demonstrated that the lncRNA AC021683.2 enhances the resistance of AML/Ara-C-resistant cells to Ara-C in vitro and in vivo, offering a potential target for treating Ara-C-resistant AML.