Coming full circle: 70 years of chronic lymphocytic leukemia cell redistribution, from glucocorticoids to inhibitors of B-cell receptor signaling

Abstract

Chronic lymphocytic leukemia (CLL) cells proliferate in pseudofollicles within the lymphatic tissues, where signals from the microenvironment and BCR signaling drive the expansion of the CLL clone. Mobilization of tissue-resident cells into the blood removes CLL cells from this nurturing milieu and sensitizes them to cytotoxic drugs. This concept recently gained momentum after the clinical activity of kinase inhibitors that target BCR signaling (spleen tyrosine kinase, Bruton tyrosine kinase, PI3K␦ inhibitors) was established. Besides antiproliferative activity, these drugs cause CLL cell redistribution with rapid lymph node shrinkage, along with a transient surge in lymphocytosis, before inducing objective remissions. Inactivation of critical CLL homing mechanism (chemokine receptors, adhesion molecules), thwarting tissue retention and recirculation into the tissues, appears to be the basis for this striking clinical activity. This effect of BCRsignaling inhibitors resembles redistribution of CLL cells after glucocorticoids, described as early as in the 1940s. As such, we are witnessing a renaissance of the concept of leukemia cell redistribution in modern CLL therapy. Here, we review the molecular basis of CLL cell trafficking, homing, and redistribution and similarities between old and new drugs affecting these processes. In addition, we outline how these discoveries are changing our understanding of CLL biology and therapy. (Blood. 2013;121(9):1501-1509) The microenvironment in CLLCirculating chronic lymphocytic leukemia (CLL) cells are nondividing resting B cells, but a significant fractions of tissue CLL cells proliferate in distinct microanatomical sites called proliferation centers or pseudofollicles, 1,2 accounting for a daily birth rate of 1%-2% of the entire CLL clone. 3 For survival and expansion, CLL cells rely on external signals from the microenvironment and normally undergo spontaneous apoptosis in tissue culture unless they are cocultured with stromal cells. 2 In the lymphatic tissues, CLL cells interact with various stromal cells, such as CD68 ϩ nurselike cells (NLC), 4-6 smooth muscle actin-positive mesenchymal stromal cells, 7 and CD4 ϩ T cells. 8,9 By inference from in vitro studies, we assume that stromal cells provide growth and survival signals to the CLL cells that are largely contact-dependent and can cooperate with intrinsic oncogenic lesions. 2,10,11 For example, interactions within the lymphatic tissue microenvironment result in BCR activation in the CLL cells, 11 and activation of this signaling cascade is favored by presence of unmutated IGHV genes and ZAP70 expression. 12 Although the affinity of CLL cells for stromal cells has long been recognized, the cross-talk between stroma and CLL cells only recently has been explored in a more systematic fashion. 11,13,14 We currently know that chemokine receptors and adhesion molecules are critical for the homing and retention of CLL cells in tissue compartments (bone marrow, secondary lymphatic tissues). 15 Gene expression profiling (GEP)...

Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110δ, for relapsed/refractory chronic lymphocytic leukemia

“…12,21 This treatment-induced lymphocytosis is not unique to idelalisib but has also been observed in patients with CLL who are administered other drugs that affect the B-cell receptor and Akt/ mTOR signaling pathways, including agents inhibiting Syk, 22 mTOR, 23 and BTK. [24][25][26] According to iwCLL 2008 criteria, a $50% increase in ALC (with a total ALC of $5.0 3 10 9 cells/L) represents CLL progression. 15 The data from this study strongly suggest that the ALC alone is not adequate as a determinant of disease status in the evaluation of novel therapeutic agents like idelalisib that cause a redistribution of CLL cells.…”

L-selectin controls trafficking of chronic lymphocytic leukemia cells in lymph node high endothelial venules in vivo

“…The tissue microenvironment is thus believed to play a critical role in CLL disease progression. [3][4][5] Indeed, a bulky lymphadenopathy is a feature of advanced disease correlating with poor clinical outcome. Importantly, CLL cell migration to LNs provides protection from chemotherapy and immunotherapy.…”

“…1,2 Accessory cells such as T cells, mesenchymal stromal cells, and nurse-like cells constitute a protective microenvironment for CLL cells in lymphoid organs. [3][4][5] They prevent the apoptosis of CLL cells and support their clonal proliferation within specific structures known as proliferation centers. The tissue microenvironment is thus believed to play a critical role in CLL disease progression.…”

The Expression of Sphingosine-1 Phosphate Receptor-1 in Chronic Lymphocytic Leukemia Cells Is Impaired by Tumor Microenvironmental Signals and Enhanced by Piceatannol and R406

“…Therefore, mobilization of tissue-resident CLL cells into the circulation is a useful strategy to minimize the reservoir of tumor cells within survival niches. This is the case for BCRassociated kinase inhibitors, such as Syk, Btk, or PI3Kd inhibitors, which, in addition to their antiproliferative activity, induce an early transient redistribution of leukemic cells from lymph nodes into the circulation upon treatment (14,27). The homing of CLL cells into lymphoid tissues has been studied in depth and involves the chemokines CXCL12, CXCL13, CCL19, and CCL21, as well as their specific receptors and diverse adhesion molecules and their ligands (28).…”