Gab2 deficiency prevents Flt3-ITD driven acute myeloid leukemia in vivo

Abstract: Internal tandem duplications (ITD) of the FMS-like tyrosine kinase 3 (FLT3) predict poor prognosis in acute myeloid leukemia (AML) and often co-exist with inactivating DNMT3A mutations. In vitro studies implicated Grb2-associated binder 2 (GAB2) as FLT3-ITD effector. Utilizing a Flt3-ITD knock-in, Dnmt3a haploinsufficient mouse model, we demonstrate that Gab2 is essential for the development of Flt3-ITD driven AML in vivo, as Gab2 deficient mice displayed prolonged survival, presented with attenuated liver and spleen pathology and reduced blast counts. Furthermore, leukemic bone marrow from Gab2 deficient mice exhibited reduced colony-forming unit capacity and increased FLT3 inhibitor sensitivity. Using transcriptomics, we identify the genes encoding for Axl and the Ret co-receptor Gfra2 as targets of the Flt3-ITD/Gab2/Stat5 axis. We propose a pathomechanism in which Gab2 increases signaling of these receptors by inducing their expression and by serving as downstream effector. Thereby, Gab2 promotes AML aggressiveness and drug resistance as it incorporates these receptor tyrosine kinases into the Flt3-ITD signaling network. Consequently, our data identify GAB2 as a promising biomarker and therapeutic target in human AML

Objekt anzeigen

• Standort: Deutsche Nationalbibliothek Frankfurt am Main
• Umfang: Online-Ressource
• Sprache: Englisch
• Anmerkungen: Leukemia. - 36 (2022) , 970–982, ISSN: 1476-5551

Beteiligte, Orts- und Zeitangaben

• Ereignis: Veröffentlichung
• (wo): Freiburg
• (wer): Universität
• (wann): 2021
• Urheber: Spohr, Corinna ; Poggio, Teresa ; Geoffroy, Andrieux ; Schönberger, Katharina ; Cabezas Wallscheid, Nina ; Börries, Melanie ; Halbach, Sebastian ; Illert, Anna Lena ; Brummer, Tilman

Weitere Informationen

• DOI: 10.1038/s41375-021-01490-0
• URN: urn:nbn:de:bsz:25-freidok-2232958
• Rechteinformation: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.