Bone marrow sites differently imprint dormancy and chemoresistance to T-cell acute lymphoblastic leukemia.

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) expands in various bone marrow (BM) sites of the body. We investigated whether different BM sites could differently modulate T-ALL propagation using in vivo animal models. We observed that mouse and human T-ALL develop slowly in the BM of tail vertebrae compared with the BM from thorax vertebrae. T-ALL recovered from tail BM displays lower cell-surface marker expression and decreased metabolism and cell-cycle progression, demonstrating a dormancy phenotype. Functionally, tail-derived T-ALL exhibit a deficient short-term ex vivo growth and a delayed in vivo propagation. These features are noncell-autonomous because T-ALL from tail and thorax shares identical genomic abnormalities and functional disparities disappear in vivo and in prolonged in vitro assays. Importantly tail-derived T-ALL displays higher intrinsic resistance to cell-cycle-related drugs (ie, vincristine sulfate and cytarabine). Of note, T-ALL recovered from gonadal adipose tissues or from cocultures with adipocytes shares metabolic, cell-cycle, and phenotypic or chemoresistance features, with tail-derived T-ALL suggesting adipocytes may participate in the tail BM imprints on T-ALL. Altogether these results demonstrate that BM sites differentially orchestrate T-ALL propagation stamping specific features to leukemic cells such as quiescence and decreased response to cell-cycle-dependent chemotherapy.

• Authors: Xavier Cahu, Julien Calvo, Sandrine Poglio, Nais Prade, Benoit Colsch, Marie-Laure Arcangeli, Thierry Leblanc, Arnaud Petit, Frederic Baleydier, Andre Baruchel, Judith Landman-Parker, Christophe Junot, Jerome Larghero, Paola Ballerini, Eric Delabesse, Benjamin Uzan, Francoise Pflumio
• Journal: Blood advances (Blood Adv) Vol. 1 Issue 20 Pg. 1760-1772 (Sep 12 2017) ISSN: 2473-9529 [Print] United States
• PMID: 29296822 (Publication Type: Journal Article)