title: ABL2 suppresses FLT3-ITD-induced cell proliferation through negative regulation of AKT signaling.
abstract: The type III receptor tyrosine kinase FLT3 is one of the most commonly mutated oncogenes in acute myeloid leukemia (AML). Inhibition of mutated FLT3 in combination with chemotherapy has displayed promising results in clinical trials. However, one of the major obstacles in targeting FLT3 is the development of resistant disease due to secondary mutations in FLT3 that lead to relapse. FLT3 and its oncogenic mutants signal through associating proteins that activate downstream signaling. Thus, targeting proteins that interact with FLT3 and their downstream signaling cascades can be an alternative approach to treat FLT3-dependent AML. We used an SH2 domain array screen to identify novel FLT3 interacting proteins and identified ABL2 as a potent interacting partner of FLT3. To understand the role of ABL2 in FLT3-mediated biological and cellular events, we used the murine pro-B cell line Ba/F3 as a model system. Overexpression of ABL2 in Ba/F3 cells expressing an oncogenic mutant of FLT3 (FLT3-ITD) resulted in partial inhibition of FLT3-ITD-dependent cell proliferation and colony formation. ABL2 expression did not alter the kinase activity of FLT3, its ubiquitination or its stability. However, it partially blocked FLT3-induced AKT phosphorylation without affecting ERK1/2 and p38 activation. Taken together our data suggest that ABL2 acts as negative regulator of signaling downstream of FLT3.
authors.affiliation: Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden.|Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: Julhash U
authors.initials: JU
authors.lastname: Kazi
authors.affiliation: Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden.|Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: Kaja
authors.initials: K
authors.lastname: Rupar
authors.affiliation: Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden.|Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: Alissa
authors.initials: A
authors.lastname: Marhäll
authors.affiliation: Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden.|Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: Sausan A
authors.initials: SA
authors.lastname: Moharram
authors.affiliation: Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden.|Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: Fatima
authors.initials: F
authors.lastname: Khanum
authors.affiliation: Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden.|Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: Kinjal
authors.initials: K
authors.lastname: Shah
authors.affiliation: Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden.|Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: Mohiuddin
authors.initials: M
authors.lastname: Gazi
authors.affiliation: Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden.|Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: Sachin Raj M
authors.initials: SR
authors.lastname: Nagaraj
authors.affiliation: Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden.|Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden.|Department of Pathogen Biology and Immunology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, P. R. China.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Sun
authors.affiliation: Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden.|Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: Rohit A
authors.initials: RA
authors.lastname: Chougule
authors.affiliation: Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden.|Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden.|Division of Oncology, Skåne University Hospital, Lund, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Rönnstrand
mesh_terms: D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D002460:Cell Line; D049109:Cell Proliferation; D051379:Mice; D009154:Mutation; D010766:Phosphorylation; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D020080:Tandem Repeat Sequences / Q000235:genetics; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics / Q000378:metabolism*
chemical_list: C426236:ARG tyrosine kinase; C497971:Flt3 protein, mouse; D011505:Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3; D051057:Proto-Oncogene Proteins c-akt
keywords: ABL2; AKT; AML; ARG; FLT3-ITD