CXCL12–CXCR4 Stromal Signaling Is Necessary for T-ALL Oncogenesis

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy with a high propensity for relapse and poor survival in children and adults. Although molecular drivers of T-ALL have been described, recent work suggests that interactions between T-ALL cells and the bone marrow microenvironment may also contribute to cell growth and survival. However, the mechanisms underlying these interactions remain unclear. Pitt, Tikhonova, and colleagues examined whether chemokine (C-X-C Motif) ligand 12 (CXCL12), a bone marrow niche chemokine that promotes hematopoietic stem cell growth, plays a similar supportive role in T-ALL carcinogenesis, and found that direct T-ALL cell interaction with CXCL12-producing vascular endothelial stromal cells was required for T-ALL maintenance and disease progression in vivo. Characterization of mouse and human T-ALL cells revealed increased cell-surface expression of CXCR4, the CXCL12 receptor, compared with healthy T cells. Inducible CXCR4 deletion or treatment with the small-molecule CXCR4 antagonist AMD3465 significantly reduced murine and human T-ALL burden and leukemia-initiating cell activity and increased overall survival via altered T-ALL cell localization, enhanced apoptosis, and decreased MYC protein expression. Consistent with these findings, Passaro and colleagues showed that CXCL12 promoted T-ALL cell motility via a mechanism dependent on calcineurin, a serine–threonine protein phosphatase previously implicated in T-ALL pathogenesis. Cell motility defects in calcineurin-deficient mice were linked to reduced CXCR4 surface expression due to downregulation of the actin-binding protein cortactin and defective CXCR4 recycling. Silencing of CXCR4 in murine or human T-ALL cells inhibited leukemia cell motility and proliferation and promoted T-ALL cell apoptosis in vitro, and impaired T-ALL cell homing in vivo, leading to decreased leukemia-initiating cell activity and suppression of leukemia engraftment. Together, these results highlight the importance of crosstalk between CXCR4-expressing T-ALL cells and CXCL12-producing stromal cells in leukemia initiation, maintenance, and progression, and provide a rationale for CXCR4 antagonists as a therapeutic strategy in T-ALL.

Pitt LA, Tikhonova AN, Hu H, Trimarchi T, King B, Gong Y, et al. CXCL12-producing vascular endothelial niches control acute T cell leukemia maintenance. Cancer Cell 2015;27:755–68.

Passaro D, Irigoyen M, Catherinet C, Gachet S, Da Costa De Jesus C, Lasgi C, et al. CXCR4 is required for leukemia-initiating cell activity in T cell acute lymphoblastic leukemia. Cancer Cell 2015;27:769–79.