The CLL Cell Microenvironment

Abstract

Cross talk between CLL cells and accessory stromal cells in specialized tissue microenvironments, such as the secondary lymphoid organs, favors CLL progression by promoting malignant B cell growth and drug resistance. Disrupting the cross talk between CLL cells and their milieu is an attractive, novel strategy for treating CLL patients. This chapter summarizes current knowledge about cellular and molecular interactions between CLL cells and their supportive tissue microenvironment and the therapeutic targets that are emerging, focusing on the CXCR4-CXCL12 axis and small molecule inhibitors that are targeting the B cell receptor-associated kinases SYK, BTK, and PI3Kδ. Clinically relevant aspects of these new therapeutics will be discussed, along with an outlook into future biologically oriented therapeutic strategies. The rapid progress in dissecting the CLL microenvironment and the promising early results of these new targeted treatments in CLL indicate that CLL has become a role model for microenvironment-dependent cancers.

EphrinA4 plays a critical role in α4 and αL mediated survival of human CLL cells during extravasation

“…In accordance with previous studies [3, 4, 6, 29–31] we demonstrate that endothelial cells can provide prosurvival signals to the leukemia cells within infiltrated tissues which are largely mediated by the release of prosurvival soluble factors. This is dependent on physical contacts between both cell types likely favored by prolonged coexistence within the infiltrated tissues.…”

Development of the Bruton's tyrosine kinase inhibitor ibrutinib for B cell malignancies

“…Safety data in patients with MCL show that more severe grade 3–4 adverse events were uncommon and that ibrutinib did not increase the incidence of grade ≥3 infections during prolonged therapy during CLL/SLL trials, compared with rates previously reported in patients receiving traditional salvage therapies . Compared with conventional chemoimmunotherapy used to treat B cell malignancies, ibrutinib is not myelosuppressive and, therefore, does not significantly impair bone marrow function––an important benefit in all patients, but particularly in elderly patients prone to cytopenic complications, including infection . The currently available data show an increase in certain bleeding events, mostly mild and moderate cases.…”

“…29,35 Compared with conventional chemoimmunotherapy used to treat B cell malignancies, ibrutinib is not myelosuppressive and, therefore, does not significantly impair bone marrow function--an important benefit in all patients, but particularly in elderly patients prone to cytopenic complications, including infection. 16,51 The currently available data show an increase in certain bleeding events, mostly mild and moderate cases. Also, atrial fibrillation has been reported in a minority of patients (3%) taking ibrutinib.…”

Pathological RANK signaling in B cells drives autoimmunity and chronic lymphocytic leukemia

“…In CLL, it is well established that the survival and expansion of tumor cells depends critically on close microenvironmental interactions with bystander cells (Burger, 2013). We have now identified the RANKL-RANK interaction as an important microenvironmental signal that promotes CLL development and CLL cell survival in the murine and human systems.…”

“…Because the crosstalk between malignant B cells and accessory cells in the microenvironment is of general importance for CLL tumor cell growth and disease progression (Burger, 2013), we next explored the role of RANKL-RANK signaling on a CLL background without the RANK K240E transgene. To this end, we first studied RANK receptor expression on CLL cells from TCL1 transgenic mice (Bichi et al, 2002) and found that these malignant cells expressed high levels of RANK on their surface, with a mean 10-fold increase compared with peripheral wt CD19 + B cells from littermate control mice (Fig.…”