Publications by authors named "N Tsakmaklis"
Waldenstrom's Macroglobulinemia (WM) is an IgM-secreting bone marrow (BM) lymphoma that is preceded by an asymptomatic state (AWM). To dissect tumor-intrinsic and immune mechanisms of progression, we perform single-cell RNA-sequencing on 294,206 BM tumor and immune cells from 30 patients with AWM/WM, 26 patients with Smoldering Myeloma, and 23 healthy donors. Despite their early stage, patients with AWM present extensive immune dysregulation, including in normal B cells, with disease-specific immune hallmarks.
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- Covalent Bruton's tyrosine kinase-inhibitors (cBTK-i) are effective in treating MYD88-mutated Waldenstrom's macroglobulinaemia by inhibiting key signaling pathways that promote tumor growth.* -
- BTK mutations can lead to treatment resistance by reactivating ERK1/2, which causes increased inflammatory cytokine production and helps BTK wild-type tumor cells survive.* -
- Pirtobrutinib, a non-covalent BTK-inhibitor, has been shown to successfully block damaging ERK1/2 activity and can overcome resistance in MYD88 lymphoma cells with mutated BTK.*
Article Synopsis
- A clinical trial was conducted to investigate the effects of combining two drugs, ibrutinib and venetoclax, for treating symptomatic, treatment-naïve patients with MYD88-mutated Waldenström macroglobulinemia (WM).
- Out of 45 patients enrolled, 42% achieved a very good partial response (VGPR), and the study noted significant adverse events, including a concerning rate of ventricular arrhythmia.
- After a median follow-up of 24.4 months, the study reported strong progression-free survival (76%) and overall survival (96%) rates, even though it was terminated early due to safety concerns.
Article Synopsis
- The HCK family kinase is upregulated and activated by mutated MYD88 in specific types of lymphomas, triggering key signaling pathways like BTK, AKT, and ERK.
- In MYD88Mut lymphoma cells, HCK enhances SYK activation, while the SFK LYN plays a lesser role in certain lymphoma types, such as Waldenstrom macroglobulinemia.
- Overexpression of HCK leads to persistent activation of SYK, and inhibiting HCK reduces SYK activity, indicating that HCK could be a potential therapeutic target for treating MYD88Mut B-cell lymphomas.