Targeting chemokines for acute lymphoblastic leukemia therapy

Abstract

Acute lymphoblastic leukemia (ALL) is a hematological malignancy characterized by the malignant clonal expansion of lymphoid hematopoietic precursors. It is regulated by various signaling molecules such as cytokines and adhesion molecules in its microenvironment. Chemokines are chemotactic cytokines that regulate migration, positioning and interactions of cells. Many chemokine axes such as CXCL12/CXCR4 and CCL25/CCR9 have been proved to play important roles in leukemia microenvironment and further affect ALL outcomes. In this review, we summarize the chemokines that are involved in ALL progression and elaborate on their roles and mechanisms in leukemia cell proliferation, infiltration, drug resistance and disease relapse. We also discuss the potential of targeting chemokine axes for ALL treatments, since many related inhibitors have shown promising efficacy in preclinical trials, and some of them have entered clinical trials.

Keywords: Acute lymphoblastic leukemia; Chemokine; Microenvironment; Therapeutic targets.

Fig. 1

Chemokines and their receptors’ roles in acute lymphoblastic leukemia. In osteoblastic niche, T-ALL cells are in direct, stable contact with vascular cells in the BM that produce CXCL12, while in vascular niche CXCL12 is secreted by several stromal cell types, especially CAR cells. Apart from the BM microenvironment, extramedullary organs such as the brain and spleen showed high expression of CCL19, which is involved in leukemic cells’ infiltration to such sites. CXCL12/CXCR4 triggers the activation of downstream kinases Src and ABL1 which are responsible for the phosphorylation of RhoGDI2, which released RhoA and RhoC, leading to subsequent cytoskeleton redistribution and assembly in the process of migration. CXCR4 could activate both ERK1/2 and PI3K/Akt pathways to promote the survival of leukemic blasts. In the homing of B cell progenitor ALL cells to the BM, CXCL12-mediated activation of p38MAPK was required and ZAP70 kinase can control the expression of CXCR4 and CCR7 via ERK1/2, which is correlated with CNS infiltration during T-ALL. CXCR4 could also activate RAC1 to mediate migration and engraftment of B-ALL cells in the BM or testicles. In addition, CXCR4 can induce the proliferation of T-ALL cells via Myc. CXCL10/CXCR3 axis may increase survival rate of leukemic cells during treatment through stabilizing Bcl-2 and inhibiting caspase activation. CXCL10 has also been proved to promote migration of leukemic cells via MMP9. The expression of CCR5 and CCR7 is regulated by Notch-1. CCR5 regulate leukemic cell’s proliferation and anti-apoptosis through JAK/STAT3 pathway. CCL25/CCR9 axis increase drug efflux-induced resistance by activating the binding of P-gp and ERM. It also facilitates the infiltration through RhoA-Rock-MLC and PI3K/AKT-RhoA pathway

Fig. 2

Acute lymphoblastic leukemia’s potential treatments targeting chemokines and their receptors. Chemokine antagonists and immunotoxins combined with chemotherapy may significantly optimize prognosis of ALL patients. CXCR4 antagonists have been proved to inhibit CXCL12-mediated chemotaxis and reverse drug resistance. AMD3100, TC14012 and BL-8040 can block the chemotactic function of the CXCL12/CXCR4 axis, interfere with the bone marrow microenvironment on which leukemia cells depend to survive, and mobilize these leukemia cells into the peripheral circulation, thereby increasing the sensitivity of leukemia cells to chemotherapeutic drugs. CCL25-PE38 fusion protein could effectively induce the apoptosis of CCR9 positive T-ALL cells. Immunotoxin PE38 is internalized via the endolysosomal system, first transported to the Golgi and further to the ER where it is activated. Activated PE38 ribosylates ADP and inactivate EF2, thus halting protein synthesis and eventually leads to apoptosis. Monoclonal antibodies 91R and 92R could inhibit the growth of T-ALL cells transplanted into immunodeficient mice. Competitive antagonist of CCR5 maraviroc inhibits CCR5-activated signaling proteins JAK and STAT3, which may lead to apoptosis, and inhibition of survival, proliferation and migration