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Therapeutic discovery for marrow failure with MDS predisposition using pluripotent stem cells
Melisa Ruiz-Gutierrez, … , Eirini P. Papapetrou, Akiko Shimamura
Melisa Ruiz-Gutierrez, … , Eirini P. Papapetrou, Akiko Shimamura
Published April 30, 2019
Citation Information: JCI Insight. 2019;4(12):e125157. https://doi.org/10.1172/jci.insight.125157.
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Research Article Hematology Therapeutics

Therapeutic discovery for marrow failure with MDS predisposition using pluripotent stem cells

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Abstract

Monosomy 7 and deletion of 7q, known as del(7q), are common clonal cytogenetic abnormalities associated with high-grade myelodysplastic syndrome (MDS) arising in inherited and acquired bone marrow failure. Current nontransplant approaches to treat marrow failure may be complicated by stimulation of clonal outgrowth. To study the biological consequences of del(7q) within the context of a failing marrow, we generated induced pluripotent stem cells (iPSCs) derived from patients with Shwachman-Diamond syndrome (SDS), a bone marrow failure disorder with MDS predisposition, and genomically engineered a 7q deletion. The TGF-β pathway was the top differentially regulated pathway in transcriptomic analysis of SDS versus SDSdel(7q) iPSCs. SMAD2 phosphorylation was increased in SDS relative to wild-type cells, consistent with hyperactivation of the TGF-β pathway in SDS. Phospho-SMAD2 levels were reduced following 7q deletion in SDS cells and increased upon restoration of 7q diploidy. Inhibition of the TGF-β pathway rescued hematopoiesis in SDS iPSCs and in bone marrow hematopoietic cells from SDS patients while it had no impact on the SDSdel(7q) cells. These results identified a potential targetable vulnerability to improve hematopoiesis in an MDS predisposition syndrome and highlighted the importance of the germline context of somatic alterations to inform precision medicine approaches to therapy.

Authors

Melisa Ruiz-Gutierrez, Özge Vargel Bölükbaşı, Gabriela Alexe, Adriana G. Kotini, Kaitlyn Ballotti, Cailin E. Joyce, David W. Russell, Kimberly Stegmaier, Kasiani Myers, Carl D. Novina, Eirini P. Papapetrou, Akiko Shimamura

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Figure 1

Generation of SDS iPSCs and SDSdel(7q) iPSCs.

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Generation of SDS iPSCs and SDSdel(7q) iPSCs.
(A and B) Representative i...
(A and B) Representative iPSC colony morphology and karyotype for SDS patient–derived iPSCs (SDS1.5) before (A) and after (B) deletion of the long arm of chromosome 7 (box) (SDS1.5D5Cre4). Karyotype analysis was performed for all iPSC lines. (C) aCGH analysis showing deletion of the chromosome 7 region between bands q11.23 and q36.3 in 1 allele. (D) Western blot analysis of SBDS protein expression in SDS1 (SDS1.5) iPSCs and SDSdel(7q) (SDS1.5D5Cre4.9#9) iPSCs compared with normal (niPS) iPSC. Actin is shown as a loading control. Numbers below the bands indicate average densitometry quantitation of the SBDS band normalized to normal control sample value. (E) Flow cytometry of pluripotency surface markers SSEA3, SSEA4, Tra-1-60, and Tra-1-81 in SDS1 iPSCs (shown in blue, SDS1.2), SDSdel(7q) iPSCs (green, SDS1.5D5Cre4.9#2), and nonpluripotent cell line (red, HEK293T). (F) The indicated iPSCs were injected into immunodeficient mice. Histology of representative teratomas derived from SDS1 (SDS1.5) iPSCs and SDSdel(7q) (SDS1.5D5Cre4.9) iPSCs show differentiation into all 3 embryonic germ layers: endoderm (left), mesoderm (middle), and ectoderm (right). Scale bar: 100 μm.

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