IKK x MDM2

B-cell prolymphocytic leukemia (B-PLL) is a rare B-cell neoplasm that presents splenomegaly, lymphocytosis, minimal or absent lymphoadenopathy, at least 55% of prolymphocytes in peripheral blood and a variable clinical course. Complex/composite karyotype and recurrent structural variants (SVs), including TP53 aberrations (mutations/deletion) and MYC abnormalities (translocation or gain) are genetic features typically seen in B-PLL. We applied the genome-wide technology of optical genome mapping (OGM) in 3 cases with B-PLL, finding multiple genomic aberrations, including SVs, copy number variations (CNVs) and aneuploidies. MYC aberrations were not observed in our cases, whereas all B-PLL showed concomitant deletion 17p and TP53 mutations. TP53-disrupted B-PLL cells showed additional genomic alterations that affect genes implicated in extrinsic and intrinsic apoptotic pathways i.e., TNFRSF10, FAS, MDM2, BCL2, and BCL2L11 and genes involved in cell-cycle regulation i.e., IKBKB, CDK2, CDK4, and RB1, suggesting that a convergent multifactorial pathogenetic mechanism may be involved in B-PLL. Applying the OGM technology on cytogenetically complex rare hematological neoplasia may be useful to improve the genetic definition and differential diagnosis of B PLL/SBLPN and related splenic B cell neoplasms.

Overexpression of P‐glycoprotein (P‐gp) in non‐small cell lung cancer (NSCLC) cells is one of the primary causes of multidrug resistance (MDR), but the molecular mechanism remains obscure. Murine double minute 2 (MDM2) has been implicated in drug resistance across multiple cancer types. In this study, we investigated the potential mechanism of MDM2 on P‐gp‐mediated MDR of NSCLC and explored the potential therapeutic effects of 20(R)‐ginsenoside Rg3 (Rg3). Western blot, RT‐PCR, and immunohistochemistry (IHC) were applied to analyze the expression of critical signaling markers. The drug accumulation in resistant cells was measured using flow cytometry and confocal microscopy. Bioinformatics analysis, co‐immunoprecipitation (co‐IP), and immunofluorescence were conducted to confirm the protein–protein interactions. MTT, colony formation, EdU, and in vivo cell line derived xenograft (CDX) models were applied to validate therapeutic agents and molecular mechanisms. We demonstrated that MDM2 acted as a positive upstream regulator of P‐gp, and the inhibition of MDM2 by Rg3 increased the sensitivity of resistant cells to taxol treatment both in vivo and in vitro. Mechanistically, we uncovered that MDM2 bound to IκB‐α, facilitating its ubiquitination degradation, which subsequently promoted NF‐κB pathway activation to drive the high expression of P‐gp. Notably, Rg3 blocked this process by inhibiting MDM2. Moreover, interference with the NF‐κB pathway reversed the regulation of P‐gp expression by MDM2. Our findings elucidate the molecular mechanisms of Rg3 in the treatment of P‐gp‐mediated MDR in NSCLC. This study also provides a new strategy to overcome P‐gp‐mediated MDR by inhibiting the MDM2‐IκB‐α signaling axis.

Arsenic is a widely distributed environmental toxicant that significantly increases the risk of developing multiple tumors. Limited information is available, however, on whether arsenic can regulate circFNDC3B to exert its toxicological responses. We provide evidence herein that circFNDC3B expression was upregulated in a dose-dependent manner in A549 cells treated with sodium arsenite. Silencing circFNDC3B suppressed A549 cell proliferation and induced apoptosis. We then examined the protein levels of key proliferation-and apoptosis-related genes within the NF-κB and p53 pathways following circFNDC3B silencing. Results demonstrated that silencing circFNDC3B significantly elevated total p53 protein levels, but reduced phosphorylation at Ser392/Ser315 and downregulation of key downstream effectors (MDM2, Bak, Bax, PUMA, p21). Critically, circFNDC3B silencing dramatically reduced the interaction between IKKβ and the NF-κB subunit p65. This impaired binding directly disrupted canonical NF-κB signaling, as evidenced by markedly diminished phosphorylation of p65 and IκBα, along with significantly decreased the expressions of downstream NF-κB target genes. These genes included pivotal anti-apoptotic factors (Bcl-2, XIAP, cIAP1, cIAP2, FLIP) and cell cycle regulators (Cyclin D1, PCNA). In conclusion, arsenic induced circFNDC3B expression, and circFNDC3B acted as anti-apoptotic and pro-survival effects through dysregulation of NF-κB pathways, potentially serving as a novel therapeutic target in lung cancer.