Journal Article

DKFZ-2023-00944

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Mast cell deficiency prevents BCR::ABL1 induced splenomegaly and cytokine elevation in a CML mouse model.

Langhammer, M. ; Schöpf, J. ; Jaquet, T. ; Horn, K. ; Angel, M. ; Spohr, C. ; Christen, D. ; Uhl, F. M. ; Maié, T. ; Jacobi, H. ; Feyerabend, T. B.DKFZ* ; Huber, J. ; Panning, M. ; Sitaru, C. ; Costa, I. ; Zeiser, R.DKFZ* ; Aumann, K. ; Becker, H.DKFZ* ; Braunschweig, T. ; Koschmieder, S. ; Shoumariyeh, K.DKFZ* ; Huber, M. ; Schemionek-Reinders, M. ; Brummer, T.DKFZ* ; Halbach, S.DKFZ*

2023
Springer Nature London

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Please use a persistent id in citations: doi:10.1038/s41375-023-01916-x

Abstract: The persistence of leukemic stem cells (LSCs) represents a problem in the therapy of chronic myeloid leukemia (CML). Hence, it is of utmost importance to explore the underlying mechanisms to develop new therapeutic approaches to cure CML. Using the genetically engineered ScltTA/TRE-BCR::ABL1 mouse model for chronic phase CML, we previously demonstrated that the loss of the docking protein GAB2 counteracts the infiltration of mast cells (MCs) in the bone marrow (BM) of BCR::ABL1 positive mice. Here, we show for the first time that BCR::ABL1 drives the cytokine independent expansion of BM derived MCs and sensitizes them for FcεRI triggered degranulation. Importantly, we demonstrate that genetic mast cell deficiency conferred by the Cpa3Cre allele prevents BCR::ABL1 induced splenomegaly and impairs the production of pro-inflammatory cytokines. Furthermore, we show in CML patients that splenomegaly is associated with high BM MC counts and that upregulation of pro-inflammatory cytokines in patient serum samples correlates with tryptase levels. Finally, MC-associated transcripts were elevated in human CML BM samples. Thus, our study identifies MCs as essential contributors to disease progression and suggests considering them as an additional target in CML therapy. Mast cells play a key role in the pro-inflammatory tumor microenvironment of the bone marrow. Shown is a cartoon summarizing our results from the mouse model. BCR::ABL1 transformed MCs, as part of the malignant clone, are essential for the elevation of pro-inflammatory cytokines, known to be important in disease initiation and progression.

Note: 2023 Jul;37(7):1474-1484

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Contributing Institute(s):

1. D110 Zelluläre Immunologie (D110)
2. DKTK Koordinierungsstelle Freiburg (FR01)

Research Program(s):

1. 314 - Immunologie und Krebs (POF4-314) (POF4-314)

Appears in the scientific report 2023

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Springer ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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