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Data from Patient-Derived iPSCs Faithfully Represent the Genetic Diversity and Cellular Architecture of Human Acute Myeloid Leukemia

Authors :
Eirini P. Papapetrou
Dan Hasson
Michael G. Kharas
Hanzhi Luo
Ravindra Majeti
Mark P. Chao
Elsa Bernard
Chan-Jung Chang
Deniz Demircioglu
Tiansu Wang
Malgorzata Olszewska
Nataly Cruz-Rodriguez
Saul Carcamo
Andriana G. Kotini
Publication Year :
2023
Publisher :
American Association for Cancer Research (AACR), 2023.

Abstract

The reprogramming of human acute myeloid leukemia (AML) cells into induced pluripotent stem cell (iPSC) lines could provide new faithful genetic models of AML, but is currently hindered by low success rates and uncertainty about whether iPSC-derived cells resemble their primary counterparts. Here we developed a reprogramming method tailored to cancer cells, with which we generated iPSCs from 15 patients representing all major genetic groups of AML. These AML-iPSCs retain genetic fidelity and produce transplantable hematopoietic cells with hallmark phenotypic leukemic features. Critically, single-cell transcriptomics reveal that, upon xenotransplantation, iPSC-derived leukemias faithfully mimic the primary patient-matched xenografts. Transplantation of iPSC-derived leukemias capturing a clone and subclone from the same patient allowed us to isolate the contribution of a FLT3-ITD mutation to the AML phenotype. The results and resources reported here can transform basic and preclinical cancer research of AML and other human cancers.Significance:We report the generation of patient-derived iPSC models of all major genetic groups of human AML. These exhibit phenotypic hallmarks of AML in vitro and in vivo, inform the clonal hierarchy and clonal dynamics of human AML, and exhibit striking similarity to patient-matched primary leukemias upon xenotransplantation.See related commentary by Doulatov.

Details

ISSN :
26433230
Database :
OpenAIRE
Accession number :
edsair.doi.dedup.....33fc29e8c0b593343a8a233028cf777d
Full Text :
https://doi.org/10.1158/2643-3230.c.6603193