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Cell Stem Cell
Article
Stage-Specific Human Induced Pluripotent
Stem Cells Map the Progression of Myeloid
Transformation to Transplantable Leukemia
Andriana G. Kotini,
1,2,3,4
Chan-Jung Chang,
1,2,3,4
Arthur Chow,
5,6,7,8
Han Yuan,
9
Tzu-Chieh Ho,
5,6,7,8
Tiansu Wang,
1,2,3,4
Shailee Vora,
1,2,3,4
Alexander Solovyov,
1,2,4,10
Chrystel Husser,
1,2,3,4
Malgorzata Olszewska,
1,2,3,4
Julie Teruya-Feldstein,
10
Deepak Perumal,
1,2,4
Virginia M. Klimek,
11
Alexandros Spyridonidis,
12
Raajit K. Rampal,
11
Lewis Silverman,
2,4
E. Premkumar Reddy,
2,4
Elli Papaemmanuil,
13
Samir Parekh,
1,2,4
Benjamin D. Greenbaum,
1,2,4,10
Christina S. Leslie,
9
Michael G. Kharas,
5,6,7,8,
* and Eirini P. Papapetrou
1,2,3,4,14,
*
1
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
2
Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
3
Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
4
Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
5
Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
6
Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
7
Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
8
Center for Experimental Therapeutics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
9
Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
10
Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
11
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
12
School of Medicine, University of Patras, Patras 26504, Greece
13
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
14
Lead Contact
*Correspondence:
kharasm@mskcc.org(M.G.K.),
eirini.papapetrou@mssm.edu(E.P.P.)
http://dx.doi.org/10.1016/j.stem.2017.01.009SUMMARY
Myeloid malignancy is increasingly viewed as a dis-
ease spectrum, comprising hematopoietic disor-
ders that extend across a phenotypic continuum
ranging from clonal hematopoiesis to myelodys-
plastic syndrome (MDS) and acute myeloid leuke-
mia (AML). In this study, we derived a collection
of induced pluripotent stem cell (iPSC) lines
capturing a range of disease stages encompass-
ing 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 pro-
gression culminating in serially transplantable
leukemia. We also show that disease stage transi-
tions, 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 un-
cover disease-stage-specific responses to drugs.
Our study therefore provides insight into the
cellular events demarcating the initiation and pro-
gression of myeloid transformation and a new
platform for testing genetic and pharmacological
interventions.
INTRODUCTION
Human hematopoiesis is sustained by hematopoietic stem and
progenitor cells (HSPCs) residing in the bonemarrow (BM) through
processes involving self-renewal, proliferation, and differentiation
to distinct cell lineages ultimately giving rise to mature functional
hematopoietic cells. Deregulation of these processes is believed
to be central to the pathogenesis of hematopoietic disorders,
which are typically grouped according to the two main blood
lineages into myeloid and lymphoid, with the former generally
classified as myeloproliferative disorders (MPDs), myelodysplas-
tic syndromes (MDSs), syndromes with overlap of the two former
categories (MDSs/MPDs), and the most dramatic, acute myeloid
leukemia (AML). AML can develop de novo or from preexisting
MPDorMDS.While the development of de novoAML frompreleu-
kemic hematopoietic stem cells (HSCs) and its progression from
MPDs (mainly chronicmyeloid leukemia [CML]) are better studied,
the development of AML fromMDS has not beenwell mapped due
to the more limited biological models of MDS and the scarcity and
poor growth of primary MDS cells, as opposed to cells fromMPD
and AML patients (Sperling et al., 2017).
Leukemogenesis has long been conceptualized as a multistep
process. All current evidence points to a model whereby MDS
and AML arise from HSPCs through the accumulation of multiple
genetic (and potentially also epigenetic) changes (Elias et al.,
2014). In recent years, deep characterization of the mutational
landscape of myeloid disorders through large-scale DNA
sequencing solidified amodel of clonal evolution through the step-
wise accumulation of mutations. Clonal tracking at high resolution
Cell Stem Cell
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, 315–328, March 2, 2017
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2017 Elsevier Inc.
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