Role of the microenvironment in pathogenesis

Chronic Lymphocytic Leukemia (CLL), a disorder characterized by the clonal expansion of B-cells in the bone marrow (BM) and secondary lymphoid tissues,¹ is the most frequently diagnosed type of leukemia in adults, with the highest rate of diagnosis seen in those aged 75–84 years.² The median age at diagnosis is 72 years and about 10% of CLL patients are reported to be younger than 55.³ Recent studies have revealed that a range of genetic alterations contribute to the tumorigenesis, clinical progression and chemo-refractoriness of CLL, and so underlie its extremely variable clinical course.⁴ Such developments have allowed the identification of new prognostic markers and patient risk stratification.

As mentioned above, CLL develops in specialized tissue microenvironments such as the BM and secondary lymphoid organs^5,6 and these environments are comprised of a number of accessory cells such as Nurselike Cells (NLCs), Bone Marrow Stromal Cells (BMSC) and T-cells. The microenvironment also comprises of signaling pathways including the B-Cell Receptor (BCR) signaling pathway and chemokine signaling.¹ The crosstalk that occurs between malignant cells and the tissue microenvironment can result in cancer progression by promoting tumor growth, proliferation, inhibition of apoptosis, and drug resistance.⁶

A growing body of evidence suggests that BCR signaling plays a crucial role in the pathogenesis of CLL.^1,6,7,8 Activation and signaling by the BCR trigger pathways that govern the fate of normal or leukemia B-cells. Furthermore, downstream BCR signaling is also evident in CLL where the signaling molecules, spleen tyrosine kinase (Syk) and PI3K, are constitutively active in the majority of CLL patients.⁸ In turn, downstream signaling pathways are induced, including calcium mobilization and activation of Akt kinase, Extracellular-Signal-Regulated Kinase 1/2 (ERK1/2), and Myeloid Leukemia Cell Differentiation Protein (MCL-1).⁹  Additionally, zeta-chain-associated protein kinase 70 (ZAP-70), which is expressed by approximately half of all CLL cases, particularly in aggressive disease cases that use unmutated IGHV genes, have been shown to enhance BCR activation and thus indicates a worse prognosis.^1,8,9 Furthermore, BCR signaling can enhance CLL cell expression of Chemokine Ligand (CCL) 3 and CCL4, which can attract additional accessory cells such as T-regulatory cells thus suggesting a role for BCR  in creating a microenvironment that in turn supports CLL cell growth and survival.

Chemokine receptor signaling has also been implicated in the pathogenesis of CLL. Chemokine receptors are critical for homing and retention of CLL cells within the tissue compartments.¹ CXCR4/CXCR12 and CXCR5, are expressed at high levels by CLL cells, which are attracted by accessory cells such as NLCs and BMSC, which can then act to provide signals for CLL cells.

Therapeutic agents that can interact with BCR signaling or chemokine– receptor signaling, or that target surface antigens selectively expressed on CLL cells, promise to have significant therapeutic benefit in CLL patients. Inhibiting pathways in the microenvironment provides an alternative approach to traditional chemotherapy, and has received much attention in recent years.¹⁰ Clinical advances include targeting various components of the BCR pathway: Bruton's tyrosine kinase (BTK; ibrutinib), PI3K (idelalisib), and Syk (fostamatinib). The CXCR4/CXCR12 pathway has also been targeted; small molecule CXCR4 (e.g. plerixafor) and CXCR12 (e.g. NOX-A12) antagonists, along with antibodies against CXCR4 (MDX-1338/BMS93656), have been developed. Additionally, immunomodulation of T-cell and Natural Killer (NK) cell responses (lenalidomide) has also been explored for the treatment of CLL.

These new therapies demonstrate promise for the treatment of CLL and highlight the importance of the microenvironment in CLL development.