PI3K/AKT confers intrinsic and acquired resistance to pirtobrutinib in chronic lymphocytic leukemia.

PURPOSE: Pirtobrutinib, a non-covalent Bruton's tyrosine kinase (BTK) inhibitor, has been approved as the first agent to overcome resistance to covalent BTK inhibitors (such as ibrutinib, acalabrutinib, and zanubrutinib). However, the mechanisms of pirtobrutinib resistance in chronic lymphocytic leukemia (CLL) remain poorly understood. METHODS: To investigate pirtobrutinib resistance, we established resistant cell models using BTK knock-out via CRISPR-Cas9 or chronic exposure to pirtobrutinib in MEC-1 cells. These models mimicked intrinsic or acquired resistance, respectively. We then analyzed differential protein expression between wild-type (WT) and resistant MEC-1 cells using Revers Phase Protein microArray (RPPA) and confirmed the findings through Western Blot. Additionally, we evaluated potential drugs to overcome pirtobrutinib resistance by conducting cell proliferation assays, apoptosis studies, and animal experiments using both sensitive and resistant cells. RESULTS: MEC-1 cells developed resistance to pirtobrutinib either through BTK knock-out or prolonged drug exposure over three months. RPPA analysis revealed significant activation of proteins related to the PI3K/AKT pathway, including AKT and S6, in the resistant cells. Western Blot confirmed increased phosphorylation of AKT and S6 in pirtobrutinib-resistant MEC-1 cells. Notably, both the PI3K inhibitor (CAL101) and the AKT inhibitor (MK2206) effectively reduced cell proliferation and induced apoptosis in the resistant cells. The anti-tumor efficacy of these drugs was mediated by inhibiting the PI3K/AKT pathway. In vivo animal studies further supported the potential of targeting PI3K/AKT to overcome both intrinsic and acquired resistance to pirtobrutinib. CONCLUSION: The PI3K/AKT pathway plays a crucial role in both intrinsic and acquired resistance to pirtobrutinib in CLL. Therapeutically targeting this pathway may offer a promising strategy to overcome pirtobrutinib resistance.

Causal relationships between circulating inflammatory factors and IgA vasculitis: a bidirectional Mendelian randomization study.

Background: IgA vasculitis (IgAV) is an immune-associated vasculitis, yet its exact etiology remains unclear. Here, we explore the interaction between IgAV and inflammatory factors using bidirectional Mendelian randomization (MR). Methods: We conducted a bidirectional summary-level MR analysis to delineate the causality of C-reactive protein (CRP), procalcitonin (PCT), and 41 circulating inflammatory regulators with IgAV. Data on genetic variants related to inflammation were obtained from three genome-wide association studies (GWASs) on CRP, PCT, and human cytokines, whereas data on IgAV was from large meta-analyses of GWAS among 216 569 FinnGen Biobank participants. The primary MR analysis was performed using the inverse-variance weighted (IVW) approach, and the sensitivity analyses were carried out using MR-Egger, weighted median, weighted mode, and MR-pleiotropy residual sum and outlier. Results: This study revealed the association of CRP higher levels with increased risk of IgAV through IVW method (Estimate odds ratio [OR] = 1.41, 95% confidence interval [CI]: 1.01-1.98, P = 0.04), MR-Egger (OR = 1.87, CI: 1.15-3.02, P = 0.01), weighted median (OR = 2.00, CI: 1.21-3.30, P = 0.01) and weighted mode (OR = 1.74, CI: 1.13-2.68, P = 0.02). Furthermore, elevated IL-8 was strongly implicated with a higher risk of IgAV (IVW OR = 1.42, CI: 1.05-1.92; P = 0.02). Conversely, genetically predicted IgAV was associated with decreased levels of TNF-ß (IVW estimate ß = -0.093, CI: -0.178 - -0.007; P = 0.033). Additionally, no such significant statistical differences for other inflammatory factors were found. Conclusion: Our current study using bidirectional MR analysis provides compelling evidence for a causal effect of CRP, PCT, and circulating inflammatory regulators on IgAV. These findings contribute to a better understanding of the pathogenesis of IgAV and emphasize the potential of targeting inflammatory factors for therapeutic interventions.

Aberrantly expressed long noncoding RNAs as potential prognostic biomarkers in newly diagnosed multiple myeloma: A systemic review and meta-analysis.

BACKGROUND: Numerous studies have manifested long noncoding RNAs (lncRNAs) as biomarkers to determine the prognosis of multiple myeloma (MM) patients. Nevertheless, the prognostic role of lncRNAs in MM is still ambiguous. Herein, we performed a meta-analysis to evaluate the predictive value of aberrantly expressed lncRNAs in MM. METHODS: A systemic literature search was performed in PubMed, EMBASE, Cochrane, and Web of Science databases until October 9, 2021, and the protocol was registered in the PROSPERO database (CRD42021284364). Our study extracted the hazard ratios (HRs) and 95% confidence intervals (CIs) of overall survival (OS), progression-free survival (PFS), or event-free survival (EFS). Begg's and Egger's tests were employed to correct publication bias. RESULT: Twenty-six individual studies containing 3501 MM patients were enrolled in this study. The results showed that aberrant expression of lncRNAs was associated with poor OS and PFS of MM patients. The pooled HRs for univariate OS and PFS were 1.48 (95% CI = 1.17-1.88, p < 0.001) and 1.30 (95% CI = 1.18-1.43, p < 0.001), respectively, whereas the pooled HRs for multivariate OS and PFS were 1.50 (95% CI = 1.16-1.95, p < 0.001) and 1.59 (95% CI = 1.22-2.07, p < 0.001), respectively. Subgroup analysis suggested that MALAT1, TCF7, NEAT1, and PVT1 upregulation were associated with poor OS (p < 0.05), PVT1, and TCF7 upregulation were implicated with worse PFS (p < 0.05), while only TCF7 overexpression was correlated with reduced EFS (p < 0.05). Moreover, the contour-enhanced funnel plot demonstrated the reliability of our current conclusion, which was not affected by publication bias. CONCLUSION: Aberrantly expressed particular lncRNAs are critical prognostic indicators in long-term survival as well as promising biomarkers in progression-free status. However, different cutoff values and dissimilar methods to assess lncRNA expression among studies may lead to heterogeneity.

PARP-1 inhibitors enhance the chemosensitivity of leukemia cells by attenuating NF-кB pathway activity and DNA damage response induced by Idarubicin

Idarubicin (IDA), an anthracycline antineoplastic drug, is commonly used in the treatment of acute myeloid leukemia (AML) with reasonable response rates and clinical benefits. However, some patients still relapse, or do not respond, and suffer high fatality rates. Recent studies have shown that overexpression of PARP-1 may represent an important risk factor in AML patients. The aim of the present study was to determine the underlying molecular mechanisms by which the PARP-1 inhibitor Olaparib enhances the chemosensitivity of the leukemia cell line K562 and THP1 to IDA. Our data demonstrated that PARP-1 is upregulated in AML patients as well as in K562 and THP1 cells, and that the suppression of PARP-1 activity by Olaparib enhances the inhibitory effect of IDA. A mechanistic study revealed that Olaparib decreases the expressions of p-ATM, p-IκBα, XIAP and p65, and upregulates Bax, cleaved-Caspase-3 and γ-H2AX. Olaparib can enhance the induction of DNA damage by IDA, probably mediated by the inhibition of the ATM-related DNA damage response. Moreover, we also found that the nuclear translocation of p65 and the nuclear export of NEMO are inhibited when IDA and Olaparib are combined. Our results suggest that Olaparib attenuates the activity of the NF-κB pathway and decreases the DNA damage response induced by IDA. Therefore, we conclude that Olaparib is a potentially valuable chemosensitizer for leukemia patients.

Systematic discrimination of the repetitive genome in proximity of ferroptosis genes and a novel prognostic signature correlating with the oncogenic lncRNA CRNDE in multiple myeloma.

Emerging insights into iron-dependent form of regulated cell death ferroptosis in cancer have opened a perspective for its use in cancer therapy. Of interest, a systematic profiling of ferroptosis gene signatures as prognostic factors has gained special attention in several cancers. Herein, we sought to investigate the presence of repetitive genomes in the vicinity of ferroptosis genes that may influence their expression and to establish a prognostic gene signature associated with multiple myeloma (MM). Our analysis showed that genes associated with ferroptosis were enriched with the repetitive genome in their vicinity, with a strong predominance of the SINE family, followed by LINE, of which the most significant discriminant values were SINE/Alu and LINE/L1, respectively. In addition, we examined in detail the performance of these genes as a cancer risk prediction model and specified fourteen ferroptosis-related gene signatures, which identified MM high-risk patients with lower immune/stromal scores with higher tumor purity in their immune microenvironment. Of interest, we also found that lncRNA CRNDE correlated with a risk score and was highly associated with the majority of genes comprising the signature. Taken together, we propose to investigate the molecular impact of the repetitive genome we have highlighted on the local transcriptome of ferroptosis genes in cancer. Furthermore, we revealed a genomic signature/biomarker related to ferroptosis that can be used to predict the risk of survival in MM patients.

Platelet and peripheral white blood cell counts at diagnosis predict the response of adult immune thrombocytopenia to recombinant human interleukin-11: A retrospective, single-center, case-control study.

This study evaluated the effectiveness of recombinant human interleukin-11 (rhIL-11) in the treatment of immune thrombocytopenia (ITP) and determined whether clinical and laboratory findings predicted the treatment response.This retrospective, single-center, case-control study included 103 adult patients with ITP treated between July 2010 and April 2014 at Jiangxi Province People's Hospital. About 49 patients in the pred+IL group received prednisone (conventional dose) combined with an rhIL-11 regimen, and 54 patients in the pred alone group received prednisone (conventional dose) alone. Demographic data, initial and follow-up platelet counts, proportions of patients achieving platelet counts ≥30 × 10/L (response) and ≥100 × 10/L (complete response) at different time points, and adverse reactions were compared between groups.Complete response rates were similar between groups overall but higher in the pred+IL group than in the pred alone group for newly diagnosed patients and those with severe ITP (P < .05). Proportions of patients achieving response or complete response at different time points were similar between groups overall but higher in the pred+IL group than in the pred alone group for newly diagnosed patients and those with severe ITP (P < .05). Posttreatment platelet count correlated negatively with platelet count at diagnosis and white blood cell (WBC) count at diagnosis in patients with newly diagnosed ITP (r = -0.337, P = .073 and r = -0.367, P = .050, respectively) or ITP with bleeding-related episodes (r = -0.357, P = .020 and r = -0.434, P = .004, respectively). No immediate or postinfusion severe adverse reactions were observed.rhIL-11 increased CR and improved hemostasis in patients with newly diagnosed or severe ITP. Platelet and WBC counts at diagnosis can predict the response to rhIL-11.