Molecular and clinical analyses of PHF6 mutant myeloid neoplasia provide their pathogenesis and therapeutic targeting.

PHF6 mutations (PHF6MT) are identified in various myeloid neoplasms (MN). However, little is known about the precise function and consequences of PHF6 in MN. Here we show three main findings in our comprehensive genomic and proteomic study. Firstly, we show a different pattern of genes correlating with PHF6MT in male and female cases. When analyzing male and female cases separately, in only male cases, RUNX1 and U2AF1 are co-mutated with PHF6. In contrast, female cases reveal co-occurrence of ASXL1 mutations and X-chromosome deletions with PHF6MT. Next, proteomics analysis reveals a direct interaction between PHF6 and RUNX1. Both proteins co-localize in active enhancer regions that define the context of lineage differentiation. Finally, we demonstrate a negative prognostic role of PHF6MT, especially in association with RUNX1. The negative effects on survival are additive as PHF6MT cases with RUNX1 mutations have worse outcomes when compared to cases carrying single mutation or wild-type.

Immune Checkpoint Inhibitor-Induced Myositis/Myasthenia Gravis Overlap.

Immune checkpoint inhibitors (ICIs) have considerably changed the management of several malignancies. Although these agents transformed the scope of management in oncology and proved long-term efficacy, they have been associated with numerous autoimmune-related adverse events. We presented a case of a 61-year-old male with a history of non-small cell lung cancer (NSCLC) who presented with respiratory failure requiring mechanical ventilation. He was discharged with a working diagnosis of myasthenia gravis crisis secondary to the use of pembrolizumab. On further evaluation, he was found to possibly have pembrolizumab-induced myositis. He was treated with plasmapheresis, methylprednisolone, and rituximab and achieved significant improvement. Pembrolizumab, a monoclonal antibody, is an ICI that targets programmed death protein 1 (PD-1), thereby blocking the interaction between PD-1 and PDL-1, leading to an enhancement of T-cell mediated immune response against tumor cells. Pembrolizumab has been used to treat a variety of malignancies including melanoma, NSCLC, and other solid tumors. Though ICIs have revolutionized the field of oncology, they should be used with caution. ICIs can cause immune-related adverse events (irAEs), including myasthenia gravis and myositis. Diagnosing irAEs is challenging due to their nonspecific presentations and lack of antibody markers. Therefore, patients and clinicians should be aware of irAEs in order to initiate timely intervention.