Speed of leukemia development and genetic diversity in xenograft models of T cell acute lymphoblastic leukemia

// Sandrine Poglio 1, 2, 3, 4 , Daniel Lewandowski 2, 3, 4, 5 , Julien Calvo 1, 2, 3, 4 , Aurelie Caye 6, 7 , Audrey Gros 8, 9 , Elodie Laharanne 8, 9 , Thierry Leblanc 10 , Judith Landman-Parker 11 , Andre Baruchel 10 , Jean Soulier 6, 12, 13 , Paola Ballerini 1, 2, 3, 4, 11 , Emmanuelle Clappier 6, 12, 13 , Francoise Pflumio 1, 2, 3, 4 1 Commissariat a l’Energie Atomique et aux Energies Alternatives (CEA), DSV-IRCM-SCSR-LSHL, UMR 967, Fontenay-aux-Roses, France 2 INSERM, U967, Fontenay-aux-Roses, France 3 Universite Paris Diderot, Sorbonne Paris Cite, UMR 967, Fontenay-aux-Roses, France 4 Universite Paris-Sud, UMR 967, Fontenay-aux-Roses, France 5 CEA, DSV-IRCM-SCSR-LRTS, UMR 967, Fontenay-aux-Roses, France 6 Universite Paris Diderot, Paris, France 7 Assistance Publique-Hopitaux de Paris (AP-HP), Departement de Genetique, UF de Genetique Moleculaire, Hopital Robert Debre Paris, France 8 INSERM, UMR1053 Bordeaux Research in Translational Oncology (BaRITOn), Bordeaux, France 9 Universite de Bordeaux, Bordeaux, France 10 AP-HP, Service d’hematologie Pediatrique, Hopital Robert Debre, Paris, France 11 AP-HP, Service d’hematologie Pediatrique, Hopital Armand Trousseau, Paris, France 12 AP-HP, Laboratoire d’Hematologie, Hopital Saint-Louis, Paris, France 13 Team Genome and Cancer, U944 INSERM, Paris, France Correspondence to: Francoise Pflumio, email: francoise.pflumio@cea.fr Sandrine Poglio, email: sandrine.poglio@u-bordeaux.fr Keywords: T-ALL, leukemia initiating cells, clonal selection, CD34, xenograft Received: June 29, 2015 Accepted: April 22, 2016 Published: May 12, 2016 ABSTRACT T cell acute lymphoblastic leukemia (T-ALL) develops through accumulation of multiple genomic alterations within T-cell progenitors resulting in clonal heterogeneity among leukemic cells. Human T-ALL xeno-transplantation in immunodeficient mice is a gold standard approach to study leukemia biology and we recently uncovered that the leukemia development is more or less rapid depending on T-ALL sample. The resulting human leukemia may arise through genetic selection and we previously showed that human T-ALL development in immune-deficient mice is significantly enhanced upon CD7 + /CD34 + leukemic cell transplantations. Here we investigated the genetic characteristics of CD7 + /CD34 + and CD7 + /CD34 − cells from newly diagnosed human T-ALL and correlated it to the speed of leukemia development. We observed that CD7 + /CD34 + or CD7 + /CD34 − T-ALL cells that promote leukemia within a short-time period are genetically similar, as well as xenograft-derived leukemia resulting from both cell fractions. In the case of delayed T-ALL growth CD7 + /CD34 + or CD7 + /CD34 − cells were either genetically diverse, the resulting xenograft leukemia arising from different but branched subclones present in the original sample, or similar, indicating decreased fitness to mouse micro-environment. Altogether, our work provides new information relating the speed of leukemia development in xenografts to the genetic diversity of T-ALL cell compartments.