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

• Published in: Leukemia Vol. 36; no. 4; pp. 970 - 982
• Main Authors: Spohr, Corinna, Poggio, Teresa, Andrieux, Geoffroy, Schönberger, Katharina, Cabezas-Wallscheid, Nina, Boerries, Melanie, Halbach, Sebastian, Illert, Anna L., Brummer, Tilman
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-04-2022; Nature Publishing Group
• Subjects: 38/91; 631/67/1990/283/1897; 631/67/395; 631/80/86; 64/110; 64/60; 692/420/755; 96/31; 96/95; Acute myeloid leukemia; Adaptor Proteins, Signal Transducing - genetics; Animals; Axl protein; Biomarkers; Bone marrow; Cancer Research; Critical Care Medicine; Drug resistance; Flt3 protein; fms-Like Tyrosine Kinase 3 - metabolism; Gab2 protein; Grb2 protein; Hematology; Humans; Intensive; Internal Medicine; Kinases; Leukemia; Leukemia, Myeloid, Acute - pathology; Medical prognosis; Medicine; Medicine & Public Health; Mice; Mutation; Oncology; Protein-tyrosine kinase; Receptor Protein-Tyrosine Kinases - metabolism; Receptors; Ret protein; Signal Transduction; Signaling; Spleen; Stat5 protein; Therapeutic targets; Transcriptomics; Tyrosine
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/s41375-021-01490-0

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.