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Background: Despite recurrent and activating mutations, including MYD88, CXCR4, ARID1A, KMT2D, and CD79B were identified, the genetic basis for Waldenström's Macroglobulinemia (WM) and the risk of progression of IgM MGUS to WM remain to be fully elucidated. Methods: We investigated the mutation status of WM (n = 8), sWM (n = 7), and IgM MGUS (n = 5) patients, by performing high‐throughput targeted AmpliSeq NGS on 117 target genes. Specifically, we analyzed the CD19+ cells from 15 WM/sWM patients and five IgM MGUS patients. We also analyzed the CD138+ cells from four WM/sWM patients and two IgM MGUS patients. Results: We detected the classic mutation MYD88L265P in 93% of WM/sWM and in 60% of IgM MGUS patients. The CXCR4S338Ter mutation was identified in 26% of WM/sWM patients, whereas it was undetectable in IgM MGUS subjects. Interestingly, we identified new mutated genes, including WNK2 somatic mutations affecting 46% of WM/sWM patients, for which a recurrent allelic variant (V1635Ter) was observed in this cohort. Moreover, sequencing evaluation revealed recurrently frameshift or missense mutations involving NFKB2 (L473Afs) in 60% of IgM MGUS and 20% of WM/sWM, PTPN13 (P1546Tfs) in 20% of IgM MGUS and 7% of WM/sWM, CARD11 (S622del) in 20% of IgM MGUS and 20% of WM/sWM, KMT2C (I823T) in all IgM MGUS and 93% of WM/sWM, and ATM in 20% of IgM MGUS and 47% of WM/sWM patients. Conclusion: In conclusion, we uncovered new insights into the mutational landscape of WM, depicting a more complex involvement of the NF‐kB pathway, and providing evidence of the recurrence of some variants (MYD88, IL17RB, NFKB2, ATM, CARD11, PTPN13, and WNK2) also in IgM MGUS. [ABSTRACT FROM AUTHOR]

Background: This review aims to provide an overview of the potential impact of fasting and diet on cancer, and in particular, on chronic lymphocytic leukemia (CLL), which is the most frequent form of leukemia in the Western world. Methods: Experimental and clinical studies have provided evidence of the crucial role of fasting in enhancing cancer treatment and improving outcomes for oncological patients, particularly at the early stages of the disease. Results: Emerging evidence highlights that fasting creates a differential stress response under critical conditions by fostering the survival of normal cells while limiting the survival and growth of cancer cells. Pivotal studies on CLL have highlighted the potential of fasting and dietary components to influence the stromal microenvironment and certain metabolic pathways, thereby affecting cancer cell apoptosis and immune response. In addition, explorative and initial clinical studies suggest that fasting and specific diets can mitigate the toxicity of chemotherapy. Conclusions: Clinical trials are needed to evaluate the efficacy and safety of nutritional and fasting approaches in cancer and CLL. Future investigations could provide new insights into the potential role of diet and fasting in the prevention and treatment of cancer, potentially leading to more effective and personalized therapeutic strategies. [ABSTRACT FROM AUTHOR]

Simple Summary: Cordycepin, an analog of adenosine, has shown anti-leukemic properties towards leukemic stem cells (LSCs) by perturbing the leukemia−stroma association. However, the full molecular picture has not been fully elucidated. In addition, Wnt/β-catenin signaling is required for LSC development and maintenance in acute myeloid leukemia (AML). Here we show that cordycepin downregulates the Wnt target genes MYC and PROM1 (CD133), critical factors in stem cell maintenance, via re-expression of WIF1 and DKK1. The results provided offer new insights into the molecular circuits involved in the cordycepin-mediated inhibition of Wnt signaling. This mechanism of action of cordycepin has potential applications in treating AML. Wnt/β-catenin signaling is critically required for the development and maintenance of leukemia stem cells (LSCs) in acute myeloid leukemia (AML) by constitutive activation of myeloid regeneration-related pathways. Cell-intrinsic activation of canonical Wnt signaling propagates in the nucleus by β-catenin translocation, where it induces expression of target oncogenes such as JUN, MYC and CCND1. As the Wnt/β−catenin pathway is now well established to be a key oncogenic signaling pathway promoting leukemic myelopoiesis, targeting it would be an effective strategy to impair LSC functionality. Although the effects of the adenosine analogue cordycepin in repressing β-catenins and destabilizing the LSC niche have been highlighted, the cellular and molecular effects on AML–LSC have not been fully clarified. In the present study, we evaluated the potency and efficacy of cordycepin, a selective repressor of Wnt/β-catenin signaling with anti-leukemia properties, on the AC133+ LSC fraction. Cordycepin effectively reduces cell viability of the AC133+ LSCs in the MUTZ−2 cell model and patient-derived cells through the induction of apoptosis. By Wnt-targeted RNA sequencing panel, we highlighted the re-expression of WIF1 and DKK1 among others, and the consequent downregulation of MYC and PROM1 (CD133) following MUTZ−2 cell exposure to increasing doses of cordycepin. Our results provide new insights into the molecular circuits involved in pharmacological inhibition mediated by cordycepin reinforcing the potential of targeting the Wnt/β-catenin and co-regulatory complexes in AML. [ABSTRACT FROM AUTHOR]