liu.seSearch for publications in DiVA
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Sipa1 deficiency-induced bone marrow niche alterations lead to the initiation of myeloproliferative neoplasm
Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska University Hospital, and.
Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska University Hospital, and.
Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska University Hospital, and.
Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska University Hospital, and.
Show others and affiliations
2018 (English)In: Blood advances, ISSN 2473-9529, Vol. 2, no 5, p. 534-548Article in journal (Refereed) Published
Abstract [en]

Mutations of signal-induced proliferation-associated gene 1 (SIPA1), a RAP1 GTPase-activating protein, were reported in patients with juvenile myelomonocytic leukemia, a childhood myelodysplastic/myeloproliferative neoplasm (MDS/MPN). Sipa1 deficiency in mice leads to the development of age-dependent MPN. However, Sipa1 expression in bone marrow (BM) microenvironment and its effect on the pathogenesis of MPN remain unclear. We here report that Sipa1 is expressed in human and mouse BM stromal cells and downregulated in these cells from patients with MPN or MDS/MPN at diagnosis. By using the Sipa1-/- MPN mouse model, we find that Sipa1 deletion causes phenotypic and functional alterations of BM mesenchymal stem and progenitor cells prior to the initiation of the MPN. Importantly, the altered Sipa1-/- BM niche is required for the development of MDS/MPN following transplantation of normal hematopoietic cells. RNA sequencing reveals an enhanced inflammatory cytokine signaling and dysregulated Dicer1, Kitl, Angptl1, Cxcl12, and Thpo in the Sipa1-/- BM cellular niches. Our data suggest that Sipa1 expression in the BM niche is critical for maintaining BM niche homeostasis. Moreover, Sipa1 loss-induced BM niche alterations likely enable evolution of clonal hematopoiesis to the hematological malignancies. Therefore, restoring Sipa1 expression or modulating the altered signaling pathways involved might offer therapeutic potential for MPN.

Place, publisher, year, edition, pages
American Society of Hematology , 2018. Vol. 2, no 5, p. 534-548
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:liu:diva-155832DOI: 10.1182/bloodadvances.2017013599PubMedID: 29514790OAI: oai:DiVA.org:liu-155832DiVA, id: diva2:1299858
Available from: 2019-03-28 Created: 2019-03-28 Last updated: 2019-03-28

Open Access in DiVA

No full text in DiVA

Other links

Publisher's full textPubMed

Authority records BETA

Sigvardsson, Mikael

Search in DiVA

By author/editor
Sigvardsson, Mikael
By organisation
Division of Microbiology and Molecular MedicineFaculty of Medicine and Health Sciences
Cell and Molecular Biology

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 3 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf