TY - JOUR
T1 - Stage-Specific Human Induced Pluripotent Stem Cells Map the Progression of Myeloid Transformation to Transplantable Leukemia
AU - Kotini, Andriana G.
AU - Chang, Chan Jung
AU - Chow, Arthur
AU - Yuan, Han
AU - Ho, Tzu Chieh
AU - Wang, Tiansu
AU - Vora, Shailee
AU - Solovyov, Alexander
AU - Husser, Chrystel
AU - Olszewska, Malgorzata
AU - Teruya-Feldstein, Julie
AU - Perumal, Deepak
AU - Klimek, Virginia M.
AU - Spyridonidis, Alexandros
AU - Rampal, Raajit K.
AU - Silverman, Lewis
AU - Reddy, E. Premkumar
AU - Papaemmanuil, Elli
AU - Parekh, Samir
AU - Greenbaum, Benjamin D.
AU - Leslie, Christina S.
AU - Kharas, Michael G.
AU - Papapetrou, Eirini P.
N1 - Funding Information:
This work was supported by NIH grants R00DK087923 and R01HL121570, Damon Runyon-Rachleff Innovation Award 30-14 from the Damon Runyon Cancer Research Foundation, the Edward P. Evans Foundation, New Scholar in Aging Award AGS-NS-0984-13 from the Ellison Medical Foundation, and research grants from the Henry and Marilyn Taub Foundation, the Babich Family Foundation, and Alex's Lemonade Stand Foundation (to E.P.P.). This work was also supported by NIH grants R01DK101989, R01CA193842, and P30CA008748, a Kimmel Scholar Award, and a V-Scholar Award (to M.G.K.). H.Y. was supported by the Tri-Institutional Training Program in Computational Biology and Medicine (NIH grant T32GM083937).
Publisher Copyright:
© 2017 Elsevier Inc.
PY - 2017/3/2
Y1 - 2017/3/2
N2 - 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.
AB - 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.
KW - acute myeloid leukemia
KW - cancer progression
KW - hPSC-derived hematopoiesis
KW - iPSC disease modeling
KW - induced pluripotent stem cells
KW - leukemia
KW - leukemia progression
KW - myelodysplastic syndrome
KW - myeloid malignancy
KW - transplantation
UR - http://www.scopus.com/inward/record.url?scp=85012921656&partnerID=8YFLogxK
U2 - 10.1016/j.stem.2017.01.009
DO - 10.1016/j.stem.2017.01.009
M3 - Article
C2 - 28215825
AN - SCOPUS:85012921656
SN - 1934-5909
VL - 20
SP - 315-328.e7
JO - Cell Stem Cell
JF - Cell Stem Cell
IS - 3
ER -