Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Feb;196(4):995-1006.
doi: 10.1111/bjh.17940. Epub 2021 Nov 18.

Dexamethasone-mediated inhibition of Notch signalling blocks the interaction of leukaemia and mesenchymal stromal cells

Helal Mohammed Mohammed Ahmed  1 , Subbaiah Chary Nimmagadda  1 , Yahya S Al-Matary  1   2 , Maren Fiori  1   2 , Tobias May  3 , Daria Frank  1   2 , Pradeep Kumar Patnana  1   2 , Christian Récher  4 , Christoph Schliemann  1 , Jan-Henrik Mikesch  1 , Thorsten Koenig  5 , Frank Rosenbauer  5 , Wolfgang Hartmann  6 , Jan Tuckermann  7 , Ulrich Dührsen  2 , Wei Lanying  1   8 , Martin Dugas  8   9 , Bertram Opalka  2 , Georg Lenz  1 , Cyrus Khandanpour  1
Affiliations

Dexamethasone-mediated inhibition of Notch signalling blocks the interaction of leukaemia and mesenchymal stromal cells

Helal Mohammed Mohammed Ahmed et al. Br J Haematol. 2022 Feb.

Abstract

Acute myeloid leukaemia (AML) is a haematological malignancy characterized by a poor prognosis. Bone marrow mesenchymal stromal cells (BM MSCs) support leukaemic cells in preventing chemotherapy-induced apoptosis. This encouraged us to investigate leukaemia-BM niche-associated signalling and to identify signalling cascades supporting the interaction of leukaemic cells and BM MSC. Our study demonstrated functional differences between MSCs originating from leukaemic (AML MSCs) and healthy donors (HD MSCs). The direct interaction of leukaemic and AML MSCs was indispensable in influencing AML cell proliferation. We further identified an important role for Notch expression and its activation in AML MSCs contributing to the enhanced proliferation of AML cells. Supporting this observation, overexpression of the intracellular Notch domain (Notch ICN) in AML MSCs enhanced AML cells' proliferation. From a therapeutic point of view, dexamethasone treatment impeded Notch signalling in AML MSCs resulting in reduced AML cell proliferation. Concurrent with our data, Notch inhibitors had only a marginal effect on leukaemic cells alone but strongly influenced Notch signalling in AML MSCs and abrogated their cytoprotective function on AML cells. In vivo, dexamethasone treatment impeded Notch signalling in AML MSCs leading to a reduced number of AML MSCs and improved survival of leukaemic mice. In summary, targeting the interaction of leukaemic cells and AML MSCs using dexamethasone or Notch inhibitors might further improve treatment outcomes in AML patients.

Keywords: acute myeloid leukaemia; bone marrow microenvironment; dexamethasone; mesenchymal stromal cell; notch.

PubMed Disclaimer

References

    1. Dohner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N Engl J Med. 2015;373(12):1136-52.
    1. Colmone A, Amorim M, Pontier AL, Wang S, Jablonski E, Sipkins DA. Leukemic cells create bone marrow niches that disrupt the behavior of normal hematopoietic progenitor cells. Science. 2008;322(5909):1861-5.
    1. Huang JC, Basu SK, Zhao X, Chien S, Fang M, Oehler VG, et al. Mesenchymal stromal cells derived from acute myeloid leukemia bone marrow exhibit aberrant cytogenetics and cytokine elaboration. Blood Cancer J. 2015;5:e302.
    1. Carlesso N, Cardoso AA. Stem cell regulatory niches and their role in normal and malignant hematopoiesis. Curr Opin Hematol. 2010;17(4):281-6.
    1. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, et al. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284(5411):143-7.

Publication types

LinkOut - more resources