Repolarization of HSC attenuates HSCs failure in Shwachman–Diamond syndrome

Sachin Kumar, Kalpana J. Nattamai, Aishlin Hassan, Amanda Amoah, Rebekah Karns, Cuiping Zhang, Ying Liang, Akiko Shimamura, M. Carolina Florian, Ute Bissels, Martha Luevano, Andreas Bosio, Stella M. Davies, Medhanie Mulaw, Hartmut Geiger, Kasiani C. Myers

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Shwachman–Diamond syndrome (SDS) is a bone marrow failure (BMF) syndrome associated with an increased risk of myelodysplasia and leukemia. The molecular mechanisms of SDS are not fully understood. We report that primitive hematopoietic cells from SDS patients present with a reduced activity of the small RhoGTPase Cdc42 and concomitantly a reduced frequency of HSCs polar for polarity proteins. The level of apolarity of SDS HSCs correlated with the magnitude of HSC depletion in SDS patients. Importantly, exogenously provided Wnt5a or GDF11 that elevates the activity of Cdc42 restored polarity in SDS HSCs and increased the number of HSCs in SDS patient samples in surrogate ex vivo assays. Single cell level RNA-Seq analyses of SDS HSCs and daughter cells demonstrated that SDS HSC treated with GDF11 are transcriptionally more similar to control than to SDS HSCs. Treatment with GDF11 reverted pathways in SDS HSCs associated with rRNA processing and ribosome function, but also viral infection and immune function, p53-dependent DNA damage, spindle checkpoints, and metabolism, further implying a role of these pathways in HSC failure in SDS. Our data suggest that HSC failure in SDS is driven at least in part by low Cdc42 activity in SDS HSCs. Our data thus identify novel rationale approaches to attenuate HSCs failure in SDS.

Original languageEnglish
Pages (from-to)1751-1762
Number of pages12
JournalLeukemia
Volume35
Issue number6
DOIs
StatePublished - Jun 2021

Bibliographical note

Funding Information:
Acknowledgements We thank Jeff Bailey and Victoria Summey from CCHMC Comprehensive Mouse and Cancer Core for their help with transplantation experiments and mouse bleed and the TTDSL at CCHMC for providing control BM MNCs samples. We thank Research Flow Cytometry Core at CCHMC for support with cell sorting and FACS analyzers. We thank the Schwachman–Diamond Syndrome registry for access to clinical data and samples. SK is currently supported by a Ramalingaswami fellowship, India at CSIR-Central Drug Research Institute, Lucknow. HG is supported by NIH grant DK104814. KCM is funded by a Conquer Cancer Foundation of ASCO Career Development Award, K12 HD028827. RNA-Seq data are archived (accession number will be provided upon publication).

Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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