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

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

doi:10.1172/jci.insight.125157

Cited by 11 publications

(10 citation statements)

References 46 publications

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“…S7D). Consistent with previous reports on other BM disorders (25,26), treatment with SD-208, a small-molecule TGF-β inhibitor, rescued the mutation-dependent reduction in clonogenicity and reverted the apoptotic phenotype of Samd9l-Mut cells, with no effect of Samd9l-WT cells (Fig. 5G, Fig.…”

Section: The Lack Of Fitness In Mutant Samd9l Cells Is Partly Mediate...supporting

confidence: 92%

Mutant Samd9l expression impairs hematopoiesis and induces bone marrow failure in mice

Abdelhamed¹,

Thomas²,

Westover³

et al. 2022

Journal of Clinical Investigation

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SAMD9 and SAMD9L germline mutations have recently emerged as a new class of predispositions to pediatric myeloid neoplasms. Patients commonly have impaired hematopoiesis, hypocellular marrows, and a greater risk of developing clonal chromosome 7 deletions leading to MDS and AML. We recently demonstrated that expressing SAMD9 or SAMD9L mutations in hematopoietic cells suppresses their proliferation and induces cell death. Here we generated a mouse model that conditionally expresses mutant Samd9l to assess the in vivo impact on hematopoiesis. Using a range of in vivo and ex vivo assays, we showed that cells with heterozygous Samd9l mutations have impaired stemness relative to wild-type counterparts, which was exacerbated by inflammatory stimuli, and ultimately led to bone marrow hypocellularity. Genomic and phenotypic analyses recapitulated many of the hematopoietic cellular phenotypes observed in patients with SAMD9 or SAMD9L mutations, including lymphopenia, and pinpointed TGF-b as a potential targetable pathway. Further, we observed non-random genetic deletion of the mutant Samd9l locus on mouse chromosome 6, mimicking chromosome 7 deletions observed in patients. Collectively, our study has enhanced our understanding of mutant Samd9l hematopoietic phenotypes, emphasized the synergistic role of inflammation in exaggerating the associated hematopoietic defects, and provided insights into potential therapeutic options for patients.

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Section: The Lack Of Fitness In Mutant Samd9l Cells Is Partly Mediate...supporting

confidence: 92%

Mutant Samd9l expression impairs hematopoiesis and induces bone marrow failure in mice

Abdelhamed¹,

Thomas²,

Westover³

et al. 2022

Journal of Clinical Investigation

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“…After adding small molecule SD208, an inhibitor of TGF-β receptor I kinase, into the culture, the hematopoiesis of SDS-iPSCs was rescued, as shown by an increase in both the number and size of erythroid and myeloid colonies. However, similar results could not be observed for the engineered del(7q) iPSCs, thereby suggesting that hiPSCs can be used to study the distinct contributions of somatic alterations [155].…”

Section: Patient-specific Ipscs For Drug Screeningmentioning

confidence: 78%

Induced Pluripotent Stem Cells as a Tool for Modeling Hematologic Disorders and as a Potential Source for Cell-Based Therapies

Pratumkaew

Issaragrisil

Luanpitpong

2021

Cells

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The breakthrough in human induced pluripotent stem cells (hiPSCs) has revolutionized the field of biomedical and pharmaceutical research and opened up vast opportunities for drug discovery and regenerative medicine, especially when combined with gene-editing technology. Numerous healthy and patient-derived hiPSCs for human disease modeling have been established, enabling mechanistic studies of pathogenesis, platforms for preclinical drug screening, and the development of novel therapeutic targets/approaches. Additionally, hiPSCs hold great promise for cell-based therapy, serving as an attractive cell source for generating stem/progenitor cells or functional differentiated cells for degenerative diseases, due to their unlimited proliferative capacity, pluripotency, and ethical acceptability. In this review, we provide an overview of hiPSCs and their utility in the study of hematologic disorders through hematopoietic differentiation. We highlight recent hereditary and acquired genetic hematologic disease modeling with patient-specific iPSCs, and discuss their applications as instrumental drug screening tools. The clinical applications of hiPSCs in cell-based therapy, including the next-generation cancer immunotherapy, are provided. Lastly, we discuss the current challenges that need to be addressed to fulfill the validity of hiPSC-based disease modeling and future perspectives of hiPSCs in the field of hematology.

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“…Generation of CN patient-specific iPSCs that recapitulate the maturation arrest of granulopoiesis has been previously described (Hiramoto et al, 2013;Morishima et al, 2014;Nayak et al, 2015). iPSCs have been used to study leukemogenesis and to identify compounds targeting AML (Chang et al, 2018;Chao et al, 2017;Hsu et al, 2019;Papapetrou, 2019;Ruiz-Gutierrez et al, 2019;Wesely et al, 2020). Using CRISPR-Cas9 gene editing, it is possible to introduce distinct mutations in iPSCs and to study stepwise, stage-specific leukemia progression (Kotini et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

iPSC modeling of stage-specific leukemogenesis reveals BAALC as a key oncogene in severe congenital neutropenia

et al. 2021

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

Cited by 11 publications

References 46 publications

Mutant Samd9l expression impairs hematopoiesis and induces bone marrow failure in mice

Mutant Samd9l expression impairs hematopoiesis and induces bone marrow failure in mice

Induced Pluripotent Stem Cells as a Tool for Modeling Hematologic Disorders and as a Potential Source for Cell-Based Therapies

iPSC modeling of stage-specific leukemogenesis reveals BAALC as a key oncogene in severe congenital neutropenia

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