TY - JOUR
T1 - Endothelial cell–leukemia interactions remodel drug responses, uncovering T-ALL vulnerabilities
AU - Cappelli, Luca Vincenzo
AU - Fiore, Danilo
AU - Phillip, Jude M.
AU - Yoffe, Liron
AU - Di Giacomo, Filomena
AU - Chiu, William
AU - Hu, Yang
AU - Kayembe, Clarisse
AU - Ginsberg, Michael
AU - Consolino, Lorena
AU - Barcia Duran, Jose Gabriel
AU - Zamponi, Nahuel
AU - Melnick, Ari M.
AU - Boccalatte, Francesco
AU - Tam, Wayne
AU - Elemento, Olivier
AU - Chiaretti, Sabina
AU - Guarini, Anna
AU - Foà, Robin
AU - Cerchietti, Leandro
AU - Rafii, Shahin
AU - Inghirami, Giorgio
N1 - Publisher Copyright:
© 2023 American Society of Hematology
PY - 2023/2/2
Y1 - 2023/2/2
N2 - T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive and often incurable disease. To uncover therapeutic vulnerabilities, we first developed T-ALL patient–derived tumor xenografts (PDXs) and exposed PDX cells to a library of 433 clinical-stage compounds in vitro. We identified 39 broadly active drugs with antileukemia activity. Because endothelial cells (ECs) can alter drug responses in T-ALL, we developed an EC/T-ALL coculture system. We found that ECs provide protumorigenic signals and mitigate drug responses in T-ALL PDXs. Whereas ECs broadly rescued several compounds in most models, for some drugs the rescue was restricted to individual PDXs, suggesting unique crosstalk interactions and/or intrinsic tumor features. Mechanistically, cocultured T-ALL cells and ECs underwent bidirectional transcriptomic changes at the single-cell level, highlighting distinct “education signatures.” These changes were linked to bidirectional regulation of multiple pathways in T-ALL cells as well as in ECs. Remarkably, in vitro EC-educated T-ALL cells transcriptionally mirrored ex vivo splenic T-ALL at single-cell resolution. Last, 5 effective drugs from the 2 drug screenings were tested in vivo and shown to effectively delay tumor growth and dissemination thus prolonging overall survival. In sum, we developed a T-ALL/EC platform that elucidated leukemia-microenvironment interactions and identified effective compounds and therapeutic vulnerabilities.
AB - T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive and often incurable disease. To uncover therapeutic vulnerabilities, we first developed T-ALL patient–derived tumor xenografts (PDXs) and exposed PDX cells to a library of 433 clinical-stage compounds in vitro. We identified 39 broadly active drugs with antileukemia activity. Because endothelial cells (ECs) can alter drug responses in T-ALL, we developed an EC/T-ALL coculture system. We found that ECs provide protumorigenic signals and mitigate drug responses in T-ALL PDXs. Whereas ECs broadly rescued several compounds in most models, for some drugs the rescue was restricted to individual PDXs, suggesting unique crosstalk interactions and/or intrinsic tumor features. Mechanistically, cocultured T-ALL cells and ECs underwent bidirectional transcriptomic changes at the single-cell level, highlighting distinct “education signatures.” These changes were linked to bidirectional regulation of multiple pathways in T-ALL cells as well as in ECs. Remarkably, in vitro EC-educated T-ALL cells transcriptionally mirrored ex vivo splenic T-ALL at single-cell resolution. Last, 5 effective drugs from the 2 drug screenings were tested in vivo and shown to effectively delay tumor growth and dissemination thus prolonging overall survival. In sum, we developed a T-ALL/EC platform that elucidated leukemia-microenvironment interactions and identified effective compounds and therapeutic vulnerabilities.
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U2 - 10.1182/blood.2022015414
DO - 10.1182/blood.2022015414
M3 - Article
C2 - 35981563
AN - SCOPUS:85146046598
SN - 0006-4971
VL - 141
SP - 503
EP - 518
JO - Blood
JF - Blood
IS - 5
ER -