Mast cell deficiency prevents BCR::ABL1 induced splenomegaly and cytokine elevation in a CML mouse model

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

Angaben zum Objekt

• Standort: Deutsche Nationalbibliothek Frankfurt am Main
• Umfang: Online-Ressource
• Sprache: Englisch
• Anmerkungen: Leukemia. - 37, 7 (2023) , 1474-1484, ISSN: 1476-5551

Beteiligte, Orts- und Zeitangaben

• Ereignis: Veröffentlichung
• (wo): Freiburg
• (wer): Universität
• (wann): 2023
• Urheber: Langhammer, Melanie ; Schöpf, Julia ; Jaquet, Timo ; Horn, Katharina ; Angel, Moritz ; Spohr, Corinna ; Christen, Daniel ; Uhl, Franziska ; Maié, Tiago ; Jacobi, Henrike ; Feyerabend, Thorsten B. ; Huber, Julia ; Panning, Marcus ; Sitaru, Cassian ; Costa, Ivan ; Zeiser, Robert ; Aumann, Konrad ; Becker, Heiko ; Braunschweig, Till ; Koschmieder, Steffen ; Shoumariyeh, Khalid ; Huber, Michael ; Huber, Michael Johannes ; Schemionek-Reinders, Mirle ; Brummer, Tilman ; Halbach, Sebastian

Weitere Informationen

• DOI: 10.1038/s41375-023-01916-x
• URN: urn:nbn:de:bsz:25-freidok-2364280
• Rechteinformation: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Letzte Aktualisierung: 25.03.2025, 13:52 MEZ