The NF-κB1/p50 Subunit Influences the Notch/IL-6-Driven Expansion of Myeloid-Derived Suppressor Cells in Murine T-Cell Acute Lymphoblastic Leukemia

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(18), С. 9882 - 9882

Опубликована: Сен. 13, 2024

T-cell acute lymphoblastic leukemia is an aggressive neoplasia due to hyper-proliferation of lymphoid progenitors and lacking a definitive cure date. Notch-activating mutations are the most common in driving disease onset progression, often combination with sustained activity NF-κB. Myeloid-derived suppressor cells represent mixed population immature exerting suppression anti-cancer immune responses tumor microenvironment many malignancies. We recently reported that transgenic murine model Notch3-dependent there accumulation myeloid-derived cells, dependent on both Notch signaling deregulation IL-6 production inside T-cells. However, possible interaction between NF-κB this context remains unexplored. Interestingly, we also Notch3 NF-κB1/p50 deleted double mutant mice display massive myeloproliferation. Here, demonstrated absence p50 subunit these dramatically enhances induction suppressive function cells. This runs parallel impressive increase concentration peripheral blood serum, depending hyper-production by T-cells from mice. Mechanistically, relies loss negative control exerted promoter. Our results reveal Notch/NF-κB cross-talk regulating cell biology leukemia, highlighting need consider carefully pleiotropic effects NF-κB-based therapy microenvironment.

Язык: Английский

Notch Inhibitors and BH3 Mimetics in T-Cell Acute Lymphoblastic Leukemia

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(23), С. 12839 - 12839

Опубликована: Ноя. 29, 2024

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with poor response to conventional therapy, derived from hematopoietic progenitors committed lineage. Relapsed/Refractory patients account for nearly 20% of childhood and 45% adult cases. Aberrant Notch signaling plays a critical role in T-ALL pathogenesis therapy resistance. inhibition promising therapeutic target personalized medicine, variety strategies prevent activation, including γ-secretase (GS) inhibitors (GSIs) antibodies neutralizing receptors or ligands, have been developed. Disruption apoptosis pivotal cancer development progression. Different reports evidenced the interplay between anti-apoptotic Bcl-2 family proteins T-ALL. Although based on early research data, this review discusses recent advances directly targeting use validated BH3 mimetics treatment their combined action light current evidence use.

Язык: Английский