Brief Report: Human Acute Myeloid Leukemia Reprogramming to Pluripotency Is a Rare Event and Selects for Patient Hematopoietic Cells Devoid of Leukemic Mutations

• Published in: Stem cells (Dayton, Ohio) Ohio), 2017-09, Vol.35 (9), p.2095-2102
• Main Authors: Lee, Jong‐Hee, Salci, Kyle R., Reid, Jennifer C., Orlando, Luca, Tanasijevic, Borko, Shapovalova, Zoya, Bhatia, Mickie
• Format: Article
• Language: English
• Subjects: Aberration; Acute myeloid leukemia; Bone Marrow Cells - pathology; Cancer; Cellular Reprogramming; Genetic diversity; Genetics; Hematopoiesis; Heterogeneity; Humans; Induced pluripotent stem cells; Induced Pluripotent Stem Cells - pathology; Leukemia; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - pathology; Mixed‐lineage leukemia; Mutation; Mutation - genetics; Myeloid leukemia; Myeloid-Lymphoid Leukemia Protein - metabolism; Oncogene Proteins, Fusion - metabolism; Pluripotency; Proteins; Reprogramming; Stem cells
• ISSN: 1066-5099; 1549-4918
• DOI: 10.1002/stem.2655

Induced pluripotent stem cell reprogramming has provided critical insights into disease processes by modeling the genetics and related clinical pathophysiology. Human cancer represents highly diverse genetics, as well as inter‐ and intra‐patient heterogeneity, where cellular model systems capable of capturing this disease complexity would be invaluable. Acute myeloid leukemia (AML) represents one of most heterogeneous cancers and has been divided into genetic subtypes correlated with unique risk stratification over the decades. Here, we report our efforts to induce pluripotency from the heterogeneous population of human patients that represents this disease in the clinic. Using robust optimized reprogramming methods, we demonstrate that reprogramming of AML cells harboring leukemic genomic aberrations is a rare event with the exception of those with de novo mixed‐lineage leukemia (MLL) mutations that can be reprogrammed and model drug responses in vitro. Our findings indicate that unlike hematopoietic cells devoid of genomic aberrations, AML cells harboring driver mutations are refractory to reprogramming. Expression of MLL fusion proteins in AML cells did not contribute to induced reprogramming success, which continued to select for patient derived cells devoid of AML patient‐specific aberrations. Our study reveals that unanticipated blockades to achieving pluripotency reside within the majority of transformed AML patient cells. Stem Cells 2017;35:2095–2102 The process of pluripotent reprogramming of acute myeloid leukemic (AML) patient derived hematopoietic cells selects for cells devoid of leukemic genomic aberrations/mutations. In contrast, generation of differentiation dysfunctional induced pluripotent stem cells (iPSCs) retaining the patient specific leukemic aberration is a rare event, in which MLL family of mutations are involved, but not sufficient.