Transmissible ER stress reconfigures the AML bone marrow compartment

Ben Doron, Sherif Abdelhamed, John T. Butler, Saman K. Hashmi, Terzah M. Horton, Peter Kurre

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Successive adaptation of the bone marrow (BM) from homeostatic hematopoietic microenvironment to a self-reinforcing niche is an integral aspect of leukemogenesis. Yet, the cellular mechanisms underlying these functional alterations remain to be defined. Here, we found that AML incursion precipitates compartmental endoplasmic reticulum (ER) stress and an unfolded protein response (UPR) in both leukemia and stromal cells. We observed that extracellular vesicles (EV) transmit ER stress in vivo from the AML xenograft to BM stroma, whereby the upregulation of core UPR components drives subsequent osteolineage differentiation of mesenchymal stem cells (MSC). Finally, we show that the underlying mechanism involves quantitative incorporation and cell–cell transfer of Bone Morphogenic Protein 2 (BMP2), a potent osteogenic signal, by AML-EVs. Corroborative studies in AML patient samples support the translational relevance of AML-EVs as a platform for BMP trafficking and source of compartmental crosstalk. Transmissible ER stress was previously identified as a source of chemoresistance in solid tumor models, and this work reveals a role in remodeling the BM niche in AML.

Original languageEnglish (US)
JournalLeukemia
DOIs
StateAccepted/In press - Jan 1 2018

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Endoplasmic Reticulum Stress
Unfolded Protein Response
Bone Marrow
Stromal Cells
Heat-Shock Proteins
Mesenchymal Stromal Cells
Heterografts
Leukemia
Up-Regulation
Bone and Bones
Neoplasms
Proteins

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Doron, B., Abdelhamed, S., Butler, J. T., Hashmi, S. K., Horton, T. M., & Kurre, P. (Accepted/In press). Transmissible ER stress reconfigures the AML bone marrow compartment. Leukemia. https://doi.org/10.1038/s41375-018-0254-2

Transmissible ER stress reconfigures the AML bone marrow compartment. / Doron, Ben; Abdelhamed, Sherif; Butler, John T.; Hashmi, Saman K.; Horton, Terzah M.; Kurre, Peter.

In: Leukemia, 01.01.2018.

Research output: Contribution to journalArticle

Doron, Ben ; Abdelhamed, Sherif ; Butler, John T. ; Hashmi, Saman K. ; Horton, Terzah M. ; Kurre, Peter. / Transmissible ER stress reconfigures the AML bone marrow compartment. In: Leukemia. 2018.
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