Stage-Specific Human Induced Pluripotent Stem Cells Map the Progression of Myeloid Transformation to Transplantable Leukemia

Publication date: Available online 16 February 2017
Source:Cell Stem Cell
Author(s): Andriana G. Kotini, Chan-Jung Chang, Arthur Chow, Han Yuan, Tzu-Chieh Ho, Tiansu Wang, Shailee Vora, Alexander Solovyov, Chrystel Husser, Malgorzata Olszewska, Julie Teruya-Feldstein, Deepak Perumal, Virginia M. Klimek, Alexandros Spyridonidis, Raajit K. Rampal, Lewis Silverman, E. Premkumar Reddy, Elli Papaemmanuil, Samir Parekh, Benjamin D. Greenbaum, Christina S. Leslie, Michael G. Kharas, Eirini P. Papapetrou
Myeloid malignancy is increasingly viewed as a disease spectrum, comprising hematopoietic disorders that extend across a phenotypic continuum ranging from clonal hematopoiesis to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). In this study, we derived a collection of induced pluripotent stem cell (iPSC) lines capturing a range of disease stages encompassing preleukemia, low-risk MDS, high-risk MDS, and secondary AML. Upon their differentiation, we found hematopoietic phenotypes of graded severity and/or stage specificity that together delineate a phenotypic roadmap of disease progression culminating in serially transplantable leukemia. We also show that disease stage transitions, both reversal and progression, can be modeled in this system using genetic correction or introduction of mutations via CRISPR/Cas9 and that this iPSC-based approach can be used to uncover disease-stage-specific responses to drugs. Our study therefore provides insight into the cellular events demarcating the initiation and progression of myeloid transformation and a new platform for testing genetic and pharmacological interventions.

Graphical abstract

Teaser

Kotini et al. integrate patient cell reprogramming with mutational analysis to assemble a panel of iPSCs capturing distinct stages across the spectrum of myeloid malignancy. They use these cells to map transformation into transplantable leukemia and study both disease progression via CRISPR/Cas9 genome editing and stage-specific effects of therapeutic agents.


http://ift.tt/2kR8vN9