Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in adults. The median age at diagnosis is 72 years, and the male to female ratio is 1.7:1. CLL is characterized by the monoclonal expansion of mature B cells with typical phenotype (CD5+ CD19+ CD20+ CD23+ sIg low) in the peripheral blood, bone marrow, and lymphoid tissues. The development of CLL is often preceded by a non-symptomatic precursor state called monoclonal B-cell lymphocytosis (MBL), defined as a monoclonal B-cell count <5 × 10⁹/L with the typical phenotype of CLL [1].

CLL is characterized by a marked degree of heterogeneity both at the clinical and at the biological level. Some patients have an indolent disease that does not require therapy for many years. Conversely, other patients have an aggressive disease that requires treatment soon after diagnosis and/or may subsequently undergo histologic transformation into an aggressive lymphoma, known as Richter syndrome [2]. The biological heterogeneity of CLL can be ascribed to the immunogenetic origin of the disease, as reflected by immunoglobulin heavy-chain (IGHV) gene status as well as to the profile of genetic alterations of proto-oncogenes and tumor-suppressor genes that are acquired by each individual patient ^[2][3][4][2,3,4].

The mutational status of IGHV genes plays a pivotal role in the biological and clinical profile of CLL. Mutated CLL (M-CLL) displays a rate of somatic hypermutation in the IGHV genes higher than 2% when compared to the corresponding germline IGHV gene counterpart, derived from post-germinal center (GC) B cells, and generally has an indolent disease course [5]. Conversely, unmutated CLL (U-CLL) displays a rate of IGHV gene somatic hypermutation lower than 2% compared to the corresponding germline IGHV gene counterpart, does not experience the GC reaction, and displays a more aggressive disease course ^[6][7][6,7]. B-cell receptor (BCR) signaling plays a fundamental pathogenic role in CLL, as documented by the biased usage of IGHV genes as well as by evidence of the dependence of CLL cell survival and growth upon BCR signaling ^[8][9][8,9]. These notions point to the BCR as a key component in CLL development and progression and as a main druggable pathway for molecular therapy with BCR inhibitors [8].

In addition to the BCR pathway, several molecular studies have identified different genetic lesions that might be used as molecular predictors or therapeutic targets ^[3][4][10][3,4,10]. The genetic landscape of CLL lacks a unifying molecular alteration, is markedly heterogeneous, and includes gross chromosomal aberrations, namely del13q14, trisomy 12, del17p13, and de11q23 as well as mutations of many cancer-related genes. The genes most frequently affected by molecular alterations in CLL cluster into specific biological pathways, including NOTCH1 signaling (NOTCH1 and FBXW7), DNA damage response (ATM, TP53, POT1), apoptosis (miR15/16 and BCL2), BCR and toll-like receptor (TLR) signaling (EGR2, BCOR, MYD88, TLR2, IKZF3), NF-κB signaling (BIRC3, NFKBIE, TRAF2, TRAF3), and RNA splicing and metabolism (SF3B1, U1, XPO1, DDX3X, RPS15) (Table 1) ^[9][11][12][9,11,12].

The continuous improvement in the understanding of CLL pathogenesis has allowed the development of novel therapies that specifically target pivotal signaling pathways of CLL cells. TIn the researcherspresent review, we cover the main biological pathways of CLL pathogenesis and the potential vulnerabilities that might be targeted in each pathway. Targeted therapy has already entered the clinical practice of CLL since several years, and its role is continuously expanding. In fact, seminal translational studies have led to understand that CLL genetic features (i.e., IGHV mutational status and TP53 abnormalities) are important biomarkers of refractoriness to chemotherapy and, therefore, act as predictors for treatment choices ^{[2][4][13][14]}[2,4,13,14]. For example, TP53 disruption and unmutated status of IGHV genes are well-established predictors of chemorefractoriness that mandate treatment with targeted agents (BCR and/or BCL2 inhibitors) that can circumvent, at least in part, the CLL refractoriness to chemo-immunotherapy (CIT). In addition, other gene mutations (i.e., NOTCH1, BIRC3) are under scrutiny in order to clearly define their prognostic and/or predictive value ^{[3][10][15][16][17]}[3,10,15,16,17].

The BCR consists of a membrane immunoglobulin non-covalently bound to a heterodimer composed of CD79α (Igα) and CD79β (Igβ). In normal B cells, antigen binding to the BCR triggers the downstream signaling cascade, thus inducing cell proliferation, survival, and differentiation stimuli (Figure 1) ^[18][19][18,19]. Compared to normal B cells, the BCR of many CLL cells is characterized by an intrinsically higher reactivity to antigens ^[20][21][20,21]. Moreover, in some cases, the BCR of CLL cells may also interact with a BCR expressed on other CLL cells, thus auto-enhancing BCR signaling ^[21][22][21,22]. About one-third of patients with CLL carry quasi-identical BCR sequences that can be classified into stereotyped BCR subsets based on the structure of their complementarity-determining regions (CDRs) ^[23][24][23,24]. Approximately 200 different CLL stereotyped BCR subsets have been identified to date [23]. These findings reinforce the notion that specific antigenic stimuli triggering the BCR may be involved in CLL pathogenesis.

The BCR is connected to a network of kinases and phosphatases that regulate and amplify its activation. Upon antigen binding, the BCR initiates a signaling cascade through the phosphorylation of Igα (CD79α) and Igβ (CD79β) by Lyn and other Src family kinases. These events are followed by the activation of other kinases, namely SYK, Bruton tyrosine kinase (BTK), and phosphoinositide-3 kinases (PI3Ks), which will transmit the signal to downstream pathways important for B-cell growth and survival, including AKT, ERK, and NF-κB (Figure 1) [19].

As stated above, BCR signaling is essential for CLL pathogenesis and proliferation and can be targeted in vivo by inhibiting the BTK that plays a pivotal role in the BCR cascade. Different BTK inhibitors (BTKi) with different modes of action are currently used or are in development in advanced stage clinical trials. In addition to BTK, PI3K is also a druggable target in CLL.