TY - JOUR
T1 - Bone marrow sites differently imprint dormancy and chemoresistance to T-cell acute lymphoblastic leukemia
AU - Cahu, Xavier
AU - Calvo, Julien
AU - Poglio, Sandrine
AU - Prade, Nais
AU - Colsch, Benoit
AU - Arcangeli, Marie Laure
AU - Leblanc, Thierry
AU - Petit, Arnaud
AU - Baleydier, Frederic
AU - Baruchel, Andre
AU - Landman-Parker, Judith
AU - Junot, Christophe
AU - Larghero, Jerome
AU - Ballerini, Paola
AU - Delabesse, Eric
AU - Uzan, Benjamin
AU - Pflumio, Francoise
N1 - Publisher Copyright:
© 2017 by The American Society of Hematology.
PY - 2017/9/12
Y1 - 2017/9/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85044641297&partnerID=8YFLogxK
U2 - 10.1182/bloodadvances.2017004960
DO - 10.1182/bloodadvances.2017004960
M3 - Article
AN - SCOPUS:85044641297
SN - 2473-9529
VL - 1
SP - 1760
EP - 1772
JO - Blood Advances
JF - Blood Advances
IS - 20
ER -