Research Papers:

ABL2 suppresses FLT3-ITD-induced cell proliferation through negative regulation of AKT signaling

Julhash U. Kazi _, Kaja Rupar, Alissa Marhäll, Sausan A. Moharram, Fatima Khanum, Kinjal Shah, Mohiuddin Gazi, Sachin Raj M. Nagaraj, Jianmin Sun, Rohit A. Chougule and Lars Rönnstrand

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Oncotarget. 2017; 8:12194-12202. https://doi.org/10.18632/oncotarget.14577

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Julhash U. Kazi1,2, Kaja Rupar1,2, Alissa Marhäll1,2, Sausan A. Moharram1,2, Fatima Khanum1,2, Kinjal Shah1,2, Mohiuddin Gazi1,2, Sachin Raj M. Nagaraj1,2, Jianmin Sun1,2,3, Rohit A. Chougule1,2, Lars Rönnstrand1,2,4

1Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden

2Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden

3Department of Pathogen Biology and Immunology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, P. R. China

4Division of Oncology, Skåne University Hospital, Lund, Sweden

Correspondence to:

Julhash U. Kazi, email: [email protected]

Lars Rönnstrand, email: [email protected]

Keywords: ABL2, ARG, FLT3-ITD, AKT, AML

Received: November 10, 2016    Accepted: December 26, 2016    Published: January 10, 2017


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.

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