JAK1 mutation

Gene expression profiling data have shownthat ALK-negative ALCL has distinctive molecular signatures, different from ALK+ ALCL and other T-cell lymphomas. Better understanding of the morphologic, immunophenotypic, genetic and molecular features of ALK-negative ALCL will help establish the correct diagnosis, guide therapeutic strategies and improve patient outcomes.

In addition, we generated a belinostat-resistant H9 cell line (H9-belino-R) by incrementally exposing H9 to increasing concentrations of belinostat...H9-belino-R retained significant resistance to other HDAC inhibitors such as romidepsin [(H9: IC50 = 0.97nM (SEM ± 0.030), H9-belino-R: IC50 = 1.38nM (SEM ± 0.028)] and panobinostat [H9: IC50 = 3.11nM (SEM ± 0.19), H9-belino-R: IC50 = 9.00nM (SEM ± 1.55)] as measured by the CellTiter-Glo Viability Assay...These preliminary findings provide us with evidence that suggests that the combination of YF2 and ruxolitinib can serve as a novel treatment combination for CTCL. Further study is planned to explore this treatment in murine models of disease.

To test sensitivity, primary or PDX cells were exposed ex vivo to a concentration range of gilteritinib (FLT3 inhibitor), trametinib (MEK1/2 inhibitor), or ruxolitinib (JAK1/2 inhibitor). This might also explain the observed sensitivity to RAS-pathway inhibition irrespective of secondary lesions. These results suggest that further research into FLT3 and RAS signalling inhibitors might lead to better treatment options for pediatric iAMP21 BCP-ALL.

Commonly used agents include low doses of methotrexate or cyclophosphamide. Ruxolitinib induced durable responses in pts with LGL and therefore may represent an option for pts requiring treatment. STAT3 mutation status was predictive of EFS and responses were associated with JAK/STAT pathway down-regulation, demonstrating on-target effects. Integrated immune profiling suggests that ruxolitinib may interrupt JAK/STAT-dependent paracrine inflammatory signals that promote bone marrow suppression.

Proteogenomics analysis identified two distinct metastasis patterns of EC associated with TME. One pattern is characterized by an immune-cold phenotype, which is predominantly observed in patients with the MSI subtype. These patients often exhibit JAK1 mutations, defects in immunoproteasome components and HLA complexes, leading to deficiencies in antigen presentation pathways, resulting in immune evasion.

We present a comprehensive clinico-genomic landscape of MSI-H/MMR-D lung cancers and demonstrate that MSI-H/MMR-D defines a rare subset of lung cancers associated with smoking, high TMB, and MLH1 inactivation. While DCB to ICI was observed in some patients, the broad range of responses suggests that clinical activity may be modulated by co-mutational landscapes.