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

Andriana G. Kotini, Saul Carcamo, Nataly Cruz-Rodriguez, Malgorzata Olszewska, Tiansu Wang, Deniz Demircioglu, Chan Jung Chang, Elsa Bernard, Mark P. Chao, Ravindra Majeti, Hanzhi Luo, Michael G. Kharas, Dan Hasson, Eirini P. Papapetrou

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

UNLABELLED: 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, p. 252. This article is highlighted in the In This Issue feature, p. 247.

Original languageEnglish
Pages (from-to)318-335
Number of pages18
JournalBlood cancer discovery
Volume4
Issue number4
DOIs
StatePublished - Jul 2023
Externally publishedYes

Keywords

  • Gene Expression Profiling
  • Genetic Variation/genetics
  • Humans
  • Induced Pluripotent Stem Cells/metabolism
  • Leukemia, Myeloid, Acute/genetics
  • Phenotype

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