Abstract 3856: Therapeutic targeting of CXCR4 in NOG mice model of human acute myeloid leukemia.
Authors: Zhang Yanyan , Patel Satyananda , Abdelouahab Hadjer , Wittner Monika , Betems Aline , Joulin Virginie , Coppo Paul , De Botton Stephane , Louache Fawzia 
Published: August 2014

Acute myeloid leukemia (AML) is a complex disease with a high mortality rate despite chemotherapy and allogeneic stem cell transplantation. It is well established that interactions between leukemic cells and the bone marrow stroma play a key role in determining whether and how any given leukemic cells will develop. Thus, many cellular and molecular elements of the microenvironment are emerging as attractive targets for therapeutic strategies.

Using mouse model of AML, previous studies reported that targeting the CXCL12/CXCR4 axis by CXCR4 inhibition in vivo could overcome the resistance of AML cells. However, these leukemic models obtained through engraftment of leukemic cell lines or transgenic cells exhibited significant levels of CXCR4 and do not represent all the heterogeneity of human AML with regard to CXCR4 expression. Indeed, we first demonstrated that AML patients are heterogeneous for CXCR4 expression and CXCL12 responsiveness suggesting that the efficiency of CXCR4 targeting might vary among patients. To evaluate whether CXCR4 inhibition could be a therapeutic option in human AML development in vivo, we first establish of spectrum of murine models using the NOG immunodeficient mice transplanted with primary patient cells characterized by a unique level of CXCR4 expression.

Seventeen sets of leukemic mice were generated using primary AML patient cells. Strikingly, xenotransplanted cells retained the fundamental biological characteristics of the original disease including the patient specific pattern of CXCR4 expression and CXCL12 mediated chemotaxis allowing addressing the roles of CXCR4 in the context of the disease heterogeneity. When high levels of CXCR4 are expressed at the surface of AML cells, blocking the receptor function with small molecule inhibitors could promote leukemic cell death and reduce NOG leukemia-initiating cells (LICs). Conversely, these drugs had no efficacy when AML cells do not express CXCR4 or when they do not respond to CXCL12. Thus, our study identified two groups of AMLs according to their positive or negative response to CXCR4 inhibitors, and demonstrates for the first time that CXCR4 blocking agents effectively antagonize CXCL12-promoted leukemic development in selected patients characterized by high CXCR4 expression and CXCL12 migratory response. These finding also showed that our leukemic xenograft models may serve as relevant tools for preclinical evaluation of novel strategies based on CXCR4 inhibition and for development of new therapeutic approach targeting the interactions between AML cells and their microenvironment.

Citation Format: Yanyan Zhang, Satyananda Patel, Hadjer Abdelouahab, Monika Wittner, Aline Betems, Virginie Joulin, Paul Coppo, Stephane De Botton, Fawzia Louache. Therapeutic targeting of CXCR4 in NOG mice model of human acute myeloid leukemia. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3856. doi:10.1158/1538-7445.AM2013-3856