The B cell receptor (BCR) signaling pathway plays a crucial role in B cell development and contributes to the pathogenesis of B cell neoplasms. In B cell malignancies, the BCR is constitutively active through both ligand-dependent and ligand-independent mechanisms, resulting in continuous Bruton tyrosine kinase (BTK) signaling activation, which provides a survival and proliferation advantage to the neoplastic clone. Among B cell malignancies, those in which the most significant results were obtained by treatment with BTK inhibitors (BTKi) include chronic lymphocytic leukemia, mantle cell lymphoma, lymphoplasmacytic lymphoma, and diffuse large B cell lymphoma. Covalent BTKi (namely ibrutinib, acalabrutinib, and zanubrutinib) functions by irreversibly blocking BTK through covalent binding to the cysteine residue 481 (Cys-481) in the ATP-binding domain. Despite the high efficacy and safety of BTKi treatment, a significant fraction of patients affected by B cell malignancies who are treated with these drugs experience disease relapse. Several mechanisms of resistance to covalent BTKi, including Cys-481 mutations of BTK, have been investigated in B cell malignancies. Non-covalent BTKi, such as pirtobrutinib, have been developed and proven effective in patients carrying both Cys-481-mutated and unmutated BTK. Moreover, targeting BTK with proteolysis-targeting chimeras (PROTACs) represents a promising strategy to overcome resistance to BTKi in B cell neoplasms.

Histological transformation (HT) into aggressive lymphoma is a turning point in a significant fraction of patients affected by indolent lymphoproliferative neoplasms, namely, chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), marginal zone lymphomas (MZLs), and lymphoplasmacytic lymphoma (LPL)

Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. Despite its indolent clinical course, therapy refractoriness and disease progression still represent an unmet clinical need. Before the advent of pathway inhibitors, chemoimmunotherapy (CIT) was the commonest option for CLL treatment and is still widely used in areas with limited access to pathway inhibitors. Several biomarkers of refractoriness to CIT have been highlighted, including the unmutated status of immunoglobulin heavy chain variable genes and genetic lesions of TP53, BIRC3 and NOTCH1. In order to overcome resistance to CIT, targeted pathway inhibitors have become the standard of care for the treatment of CLL, with practice-changing results obtained through the inhibitors of Bruton tyrosine kinase (BTK) and BCL2. However, several acquired genetic lesions causing resistance to covalent and noncovalent BTK inhibitors have been reported, including point mutations of both BTK (e.g., C481S and L528W) and PLCG2 (e.g., R665W). Multiple mechanisms are involved in resistance to the BCL2 inhibitor venetoclax, including point mutations that impair drug binding, the upregulation of BCL2-related anti-apoptotic family members, and microenvironmental alterations. Recently, immune checkpoint inhibitors and CAR-T cells have been tested for CLL treatment, obtaining conflicting results. Potential refractoriness biomarkers to immunotherapy were identified, including abnormal levels of circulating IL-10 and IL-6 and the reduced presence of CD27⁺CD45RO⁻ CD8⁺ T cells.

Richter transformation (RT) represents a rare but highly lethal evolution of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), most frequently manifesting as diffuse large B-cell lymphoma (DLBCL). Despite therapeutic advances in CLL, DLBCL-RT remains characterized by rapid progression, profound treatment refractoriness, and short survival with conventional chemoimmunotherapy, underscoring the need for a refined biological and therapeutic framework. A defining feature of RT is clonal relatedness: most cases arise through linear or branched evolution of the antecedent CLL clone and carry an inferior prognosis compared with clonally unrelated cases that resemble de novo DLBCL. Recent multi-omic data further indicate that clonally related RT commonly originates from minute, transformation-primed subclones detectable years before clinical emergence, shifting RT from a late stochastic event to an early-established evolutionary trajectory. At transformation, recurrent genetic lesions of TP53, CDKN2A/B, NOTCH1, and MYC cooperate with B-cell receptor-associated programs, epigenetic reconfiguration, and metabolic rewiring toward OXPHOS- and mTOR-driven states, collectively promoting genomic instability and aggressive growth. In parallel, RT develops within a profoundly immunosuppressive microenvironment marked by PD-1-expressing malignant B cells, PD-L1-rich myeloid niches, exhausted T cells, expanded regulatory T cells, and M2-skewed macrophages interconnected by redundant checkpoint and cytokine networks. Therapeutic strategies are rapidly evolving, including pathway inhibitors, immune checkpoint blockade, T-cell-engaging bispecific antibodies, CAR-T therapies, and antibody–drug conjugates. This review integrates current insights into RT pathogenesis, immune escape, and emerging therapies, highlighting opportunities for biomarker-driven patient stratification, rational combinations, and earlier interception of transformation-prone disease.

الخلفية العلمية: ابيضاض الدم النخاعي الحاد (AML) هو أحد أكثر الأورام الدموية الخبيثة فتكًا و تتميز بوظائف خلوية غير طبيعية وتغيرات جينية. و تبين ان الطفرات في جينات نازعة هيدروجين إيزوسيترات (IDH) وخاصة IDH1 و IDH2 ، على أنها تشوهات وراثية متكررة في مرضى ابيضاض الدم النخاعي الحاد .و تؤدي هذه الطفرات إلى نشاط إنزيمي غير طبيعي، مما يؤدي إلى تراكم 2-هيدروكسي جلوتارات (2-HG)،,والذي بدوره يعطل العمليات الخلوية الطبيعية بما في ذلك مثيلة الحمض النووي. الهدف: تهدف مقالة المراجعة هذه إلى استعراض الطفرات الجينية المسجلة لـ, IDH التحقق من العلاقة بين تلك الطفرات والتغييرات في أنماط مثيلة الحمض النووي، وآثارها على التسبب في الإصابة بابيضاض الدم النخاعي الحاد والتنبؤ به وعلاجه. المواد وطرق العمل: تم إجراء بحث شامل في الأدبيات العلمية لتحديد الدراسات ذات الصلة التي تبحث في تأثير طفرات IDH على الجينات المرتبطة بمثيل الحمض النووي في المرضى الذين يعانون من ابيضاض الدم. وتمت مراجعة الدراسات المختارة وتحليلها لغرض الوصول الى المعلومات والمعرفة الحالية حول هذا الموضوع. النتائج: سلطت هذه المقالة الضوء على أن طفرات IDH في AML مرتبطة بتغيرات واسعة...

CD40 is a type 1 transmembrane protein composed of 277 amino acids, and it belongs to the tumor necrosis factor receptor (TNFR) superfamily. It is expressed in a variety of cell types, including normal B cells, macrophages, dendritic cells, and endothelial cells, as a costimulatory molecule. This study aims to summarize the CD40 polymorphism effect and its susceptibility to immune-related disorders. The CD40 gene polymorphisms showed a significant association with different immune-related disorders and act as a risk factor for increased susceptibility to these diseases.