CLL is a monoclonal proliferation of mature B lymphocytes defined by an absolute clonal count ≥5 × 10⁹/L in blood. CLL is clinically heterogeneous: some patients remain asymptomatic for years, whereas others need multiple lines of therapy. BCR biology and immunogenetics. A central driver of CLL biology is B-cell receptor (BCR) signaling. Compared with normal B cells, CLL cells display low IgM expression, variable responses to antigen, and tonic activation of anti-apoptotic pathways. Gene-expression and tissue array studies show up-regulation of BCR-pathway genes in lymph nodes and marrow versus blood, highlighting microenvironmental homing. The IGHV mutation status is a key immunogenetic marker: about 60% of patients have IGHV mutated ≥2% from germline (typically indolent course), while ∼40% have unmutated IGHV (<2%), associated with faster progression and shorter survival before the era of BCR-targeted therapies. Roughly 30% of cases carry stereotyped BCRs; certain stereotyped subsets (e.g., 1 and 2) predict higher-risk disease. Cytogenetic lesions. Recurrent abnormalities identified by FISH (and, when needed, stimulated metaphase karyotype) include del(13q14.3) (most common; favorable when isolated), trisomy 12 (intermediate risk), del(11q22.3) involving ATM (bulky nodes, aggressive disease in younger patients), and del(17p13.1) affecting TP53 (worst prognosis, poor response to traditional chemotherapy). Complex karyotype (≥3 abnormalities) adversely impacts time to treatment and overall survival. Because clonal evolution can occur even without therapy, FISH (± cytogenetics) should be reassessed before each line of treatment, particularly to detect new del(17p). Gene mutations and microRNAs. CLL genomes are relatively simple (≈20 nonsynonymous changes and ≈5 structural lesions on average) and lack a unifying driver. Recurrently mutated genes include SF3B1, NOTCH1, MYD88, ATM, and TP53. NOTCH1 mutations (∼15%) often co-occur with trisomy 12 and may confer reduced sensitivity to anti-CD20 antibodies and increased risk of Richter transformation; SF3B1 relates to DNA-damage responses; TP53 mutations rise from ∼5% in early untreated disease to ∼40% in advanced disease, frequently coexisting with del(17p). ATM mutations (10–15%) often accompany del(11q). MYD88 mutations are enriched in IGHV-mutated CLL and associate with a more indolent course. Non-coding alterations are also relevant: del(13q14.3) deletes the miR-15/16 cluster, derepressing anti-apoptotic programs (e.g., BCL2); loss of miR-181a and over-expression of miR-155 further support leukemic survival. Immune dysregulation. Beyond the malignant clone, CLL features innate and adaptive immune defects: reduced complement, qualitative neutrophil and NK-cell dysfunction, CD4⁺ T-cell exhaustion with impaired cytotoxicity, Th1→Th2 polarization, and T-regulatory expansion. Hypogammaglobulinemia is common (≈85% over the disease course), with low IgG/IgA correlating with infections. Diagnosis and differential. CLL is most often detected incidentally via lymphocytosis. Flow cytometry confirms a characteristic phenotype—CD19⁺, CD20 (dim), CD22⁺, CD23⁺, CD200⁺, CD5⁺, with dim surface Ig (kappa or lambda). When blood clonal B cells are ≥5 × 10⁹/L, no additional testing is needed to confirm CLL. Take-home. Integrating flow cytometry, cytogenetics (FISH/karyotype), and targeted sequencing with IGHV status and non-coding lesions underpins modern risk stratification and sharpens diagnostic certainty in CLL.