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Chronic lymphocytic leukemia (CLL) is an incurable B-cell neoplasm characterized by highly variable clinical outcomes. In recent years, genomic and molecular studies revealed a remarkable heterogeneity in CLL, which mirrored the clinical diversity of this disease. These studies profoundly enhanced our understanding of leukemia cell biology and led to the identification of new biomarkers with potential prognostic and therapeutic significance. Accumulating evidence indicates a key role of deregulated NOTCH1 signaling and NOTCH1 mutations in CLL. This review highlights recent discoveries that improve our understanding of the pathophysiological NOTCH1 signaling in CLL and the clinical impact of NOTCH1 mutations in retrospective and prospective trials. In addition, we discuss the rationale for a therapeutic strategy aiming at inhibiting NOTCH1 signaling in CLL, along with an overview on the currently available NOTCH1-directed approaches. [ABSTRACT FROM AUTHOR]

To investigate chronic lymphocytic leukemia (CLL)-initiating cells, we assessed NOTCH1 mutation/expression in hematopoietic stem cells (HSCs). In NOTCH1-mutated CLL, we detected subclonal mutations in 57% CD34+/CD38- HSCs. NOTCH1 mutation was present in 66% CD34+/CD38+ progenitor cells displaying an increased mutational burden compared to HSCs. Flow cytometric analysis revealed significantly higher NOTCH1 activation in CD34+/CD38- and CD34+/CD38+ cells from CLL patients, regardless NOTCH1 mutation compared to healthy donors. Activated NOTCH1 resulted in overexpression of the NOTCH1 target c-MYC. We conclude that activated NOTCH1 is an early event in CLL that may contribute to aberrant HSCs in this disease. [ABSTRACT FROM AUTHOR]

Background aims The impact of chronic lymphatic leukemia (CLL) tumor burden on the autologous immune system has already been demonstrated. This study attempted to elucidate the molecular mechanisms underlying T-cell immunologic deficiencies in CLL. Methods Freshly isolated CD3+ T cells from patients with a diagnosis of CLL and healthy donors were analyzed by gene expression profiling. Activated T cells from 20 patients with CLL were tested in vitro for cytotoxicity against mutated and unmutated autologous B cells and DAUDI, K562 and P815 cell lines. To investigate T-cell mediated cytotoxicity in vivo, we co-transplanted OKT3-activated T lymphocytes and autologous B-cell CLL (B-CLL) cells into NOD/SCID mice. Results Gene expression profiles of peripheral blood T cells from B-CLL patients showed 25 down-regulated, and 31 up-regulated, genes that were mainly involved in cell differentiation, proliferation, survival, apoptosis, cytoskeleton formation, vesicle trafficking and T-cell activation. After culture, the T-cell count remained unchanged, CD8 cells expanded more than CD4 and a cytotoxicity index >30% was present in 5/20 patients. Cytotoxicity against B autologous leukemic cells did not correlate with B-cell mutational status. Only activated T cells exerting cytotoxicity against autologous leukemic B cells prevented CLL in a human-mouse chimera. Conclusions This study indicates that patients with CLL are affected by a partial immunologic defect that might be somewhat susceptible to repair. This study identifies the molecular pathways underlying T-cell deficiencies in CLL and shows that cytotoxic T-cell functions against autologous B-CLL can be rebuilt at least in part in vitro and in vivo. [ABSTRACT FROM AUTHOR]

The article presents a case study of a novel NOTCH1 mutation of the proline, glutamic acid, serine and threonine (PEST) domain in a 65-year-old male with chronic lymphocytic leukemia (CLL). He received three cycles of hemoimmunotherapy with rituximab and fludarabine due to disease progression. He died after one month due to worsening of his conditions associated with persistent thrombocytopenia, anemia and lymphocytosis.

The article offers information on the advancement in the process of diagnosis, prognosis, and treatment of B-cell chronic lymphocytic leukaemia (B-CLL). It mentions that high expression of zeta-chain-associated protein kinase 70 (ZAP-70) and unmutated immunoglobulin heavy variable (IGHV) genes are considered poor factors for prognosis. It informs that NOTCH1 and PEST mutations are considered as marker of poor prognosis in a minority of B-CLL patients.

The article reports on a study determining whether NOTCH1 activating mutations are present in B-chronic lymphocytic leukemia (B-CLL) cells. As reported, Notch1 and Notch2 constitutive activation plays a critical role in survival and apoptosis resistance of B-CLL cells. It has been suggested in the study that for T-cell acute lymphoblastic leukemia (T-ALL), deletions of the COOH-terminal sequences in the PEST domain could enhance Notch-IC stability and signalling.