The advent of next-generation sequencing technologies has unveiled a new window into the heterogeneity of acute myeloid leukemia (AML). In particular, recurrent mutations in spliceosome machinery and genome-wide aberrant splicing events have been recognized as a prominent component of this disease. This review will focus on how these factors influence drug resistance through altered splicing of tumor suppressor and oncogenes and dysregulation of the apoptotic signaling network. A better understanding of these factors in disease progression is necessary to design appropriate therapeutic strategies recognizing specific alternatively spliced or mutated oncogenic targets.

Earlier studies have demonstrated a functional link between B56γ-specific protein phosphatase 2A (B56γ-PP2A) and p53 tumor suppressor activity. Upon DNA damage, a complex including B56γ-PP2A and p53 is formed which leads to Thr55 dephosphorylation of p53, induction of the p53 transcriptional target p21, and the inhibition of cell proliferation. Although an enhanced interaction between p53 and B56γ is observed after DNA damage, the underlying mechanism and its significance in PP2A tumor-suppressive function remain unclear. In this study, we show that the increased interaction between B56γ and p53 after DNA damage requires ATM-dependent phosphorylation of p53 at Ser15. In addition, we demonstrate that the B56γ3-induced inhibition of cell proliferation, induction of cell cycle arrest in G₁, and blockage of anchorage-independent growth are also dependent on Ser15 phosphorylation of p53 and p53-B56γ interaction. Taken together, our results provide a mechanistic link between Ser15 phosphorylation-mediated p53-B56γ interaction and the modulation of p53 tumor suppressor activity by PP2A. We also show an important link between ATM activity and the tumor-suppressive function of B56γ-PP2A.

Although CD20×CD3 bispecific antibodies are effective against systemic B-cell lymphomas, their efficacy in central nervous system (CNS) lymphoma is unknown. Here, we report the CD20×CD3 bispecific glofitamab penetrates the blood-brain barrier, stimulates immune-cell infiltration of CNS tumors, and induces clinical responses in patients with secondary CNS.

Purpose: Comorbid medical conditions define a subset of patients with chronic lymphocytic leukemia (CLL) with poor outcomes. However, which comorbidities are most predictive remains understudied. Experimental Design: We conducted a retrospective analysis from 10 academic centers to ascertain the relative importance of comorbidities assessed by the cumulative illness rating scale (CIRS). The influence of specific comorbidities on event-free survival (EFS) was assessed in this derivation dataset using random survival forests to construct a CLL-specific comorbidity index (CLL-CI). Cox models were then fit to this dataset and to a single-center, independent validation dataset. Results: The derivation and validation sets comprised 570 patients (59% receiving Bruton tyrosine kinase inhibitor, BTKi) and 167 patients (50% receiving BTKi), respectively. Of the 14 CIRS organ systems, three had a strong and stable influence on EFS: any vascular, moderate/severe endocrine, moderate/severe upper gastrointestinal comorbidity. These were combined to create the CLL-CI score, which was categorized into 3 risk groups. In the derivation dataset, the median EFS values were 58, 33, and 20 months in the low, intermediate, and high-risk groups, correspondingly. Two-year overall survival (OS) rates were 96%, 91%, and 82%. In the validation dataset, median EFS values were 81, 40, and 23 months (two-year OS rates 97%/92%/88%), correspondingly. Adjusting for prognostic factors, CLL-CI was significantly associated with EFS in patients treated with either chemo-immunotherapy or with BTKi in each of our 2 datasets. Conclusions: The CLL-CI is a simplified, CLL-specific comorbidity index that can be easily applied in clinical practice and correlates with survival in CLL.