Oral Presentation 28th Lorne Cancer Conference 2016

Chemokine receptor CXCR4 is required for progression of T cell acute lymphoblastic leukemia (#20)

Lauren A Pitt 1 , Anastasia N Tikhonova 2 , Hai Hu 2 , Thomas Trimarchi 2 , Bryan King 2 , Yixiao Gong 2 , Marta Sanchez-Martin 3 , Aris Tsirigos 2 , Dan R Littman 1 , Adolfo A Ferrando 3 , Sean J Morrison 4 , David R Fooksman 5 , Iannis Aifantis 2 , Susan R Schwab 1
  1. Skirball Institute, NYU School of Medicine, New York, NY, USA
  2. Department of Pathology, NYU School of Medicine, New York, NY, USA
  3. Institute for Cancer Genetics, Columbia University, New York, NY, USA
  4. Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA
  5. Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA
Of the most common childhood cancer, acute lymphoblastic leukemia (ALL), 15% of cases are caused by transformation of T cell progenitors (T-ALL). While survival rates have vastly improved for newly diagnosed T-ALL, substantial challenges remain in the treatment of relapsed disease and in the minimization of side-effects from central nervous system prophylaxis. Hence, the search for more effective, less toxic treatments continues. Homing receptors play multiple roles in cancer progression, yet little is known about the trafficking of T-ALL. Upon profiling homing receptor expression, we found high levels of the chemokine receptor CXCR4 on the surface of mouse and primary human T-ALL cells. Furthermore, T-ALL cells localized in close proximity to CXCL12-producing stromal cells in mouse femoral bone marrow. Deletion of CXCL12 in vascular endothelial cells limited leukemia progression, suggesting a vascular niche for T-ALL. In parallel, we found CXCR4 expression to be essential for T-ALL maintenance and progression. Deletion of Cxcr4 in mouse T-ALL after disease onset led to disease remission and prolonged survival, and CXCR4 antagonism using the small molecule inhibitor AMD3465 suppressed human disease in a patient-derived xenograft model. Loss of CXCR4 signalling in T-ALL cells reduced Myc abundance, which was previously reported to regulate leukemia-initiating cell activity. In line with this, CXCR4-deficient T-ALL cells failed to establish disease when adoptively transferred into secondary hosts. Together, our findings highlight an important contribution of microenvironment in regulating T-ALL pathogenesis, and suggest targeting CXCL12:CXCR4 signalling as a powerful new strategy for treating this aggressive disease.