GSE210889
Patient-derived iPSCs faithfully represent the genetic diversity and cellular architecture of human acute myeloid leukemia
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. Overall design: Single-cell RNA-sequencing was performed with the Chromium 10x Genomics 3' protocol (v3.0) on cryopreserved primary AML patient PBMCs, iPSC-HSPCs from day 11 (AML-9.9 and AML-47.1) or day 17 (AML-4.10) of differentiation and hCD45+ cells from primary and iPSC-derived xenografts sorted using Magnetic Activated Cell Sorting.