Abstract
Fms-like tyrosine kinase (FLT3) is a frequently mutated oncogene in acute myeloid leukemia (AML). FLT3 inhibitors display promising results in a clinical setting, but patients relapse after short-term treatment due to the development of resistant disease. Therefore, a better understanding of FLT3 downstream signal transduction pathways will help to identify an alternative target for the treatment of AML patients carrying oncogenic FLT3. Activation of FLT3 results in phosphorylation of FLT3 on several tyrosine residues that recruit SH2 domain-containing signaling proteins. We screened a panel of SH2 domain-containing proteins and identified SLAP2 as a potent interacting partner of FLT3. We demonstrated that interaction occurs when FLT3 is activated, and also, an intact SH2 domain of SLAP2 is required for binding. SLAP2 binding sites in FLT3 mainly overlap with those of SRC. SLAP2 over expression in murine proB cells or myeloid cells inhibited oncogenic FLT3-ITD-mediated cell proliferation and colony formation in vitro, and tumor formation in vivo. Microarray analysis suggests that higher SLAP2 expression correlates with a gene signature similar to that of loss of oncogene function. Furthermore, FLT3-ITD positive AML patients with higher SLAP2 expression displayed better prognosis compared to those with lower expression of SLAP2. Expression of SLAP2 blocked FLT3 downstream signaling cascades including AKT, ERK, p38 and STAT5. Finally, SLAP2 accelerated FLT3 degradation through enhanced ubiquitination. Collectively, our data suggest that SLAP2 acts as a negative regulator of FLT3 signaling and therefore, modulation of SLAP2 expression levels may provide an alternative therapeutic approach for FLT3-ITD positive AML.
Highlights
Acute myeloid leukemia (AML) is a hematopoietic disorder originating from the myeloid lineage [1]
Our data suggest that SLAP2 acts as a negative regulator of FLT3 signaling and modulation of SLAP2 expression levels may provide an alternative therapeutic approach for FLT3-internal tandem duplication (ITD) positive acute myeloid leukemia (AML)
We showed that SLAP2 acts as a negative regulator of FLT3 signaling
Summary
Acute myeloid leukemia (AML) is a hematopoietic disorder originating from the myeloid lineage [1]. Multiple genetic alterations including loss-of-function mutations in transcription factors and gain-of-function mutations in receptor tyrosine kinases are well-known genetic changes in AML. FLT3 belongs to the type III receptor tyrosine kinase family with the other members including PDGFRA, PDGFRB, KIT, and CSF1R. Key features of this family of proteins include an extracellular ligand-binding domain, a transmembrane domain, a juxtamembrane domain and a kinase domain separated by a short kinase insert. Association of GRB10, SYK and SRC family kinases to FLT3 enhances downstream signaling, while SOCS2, SOCS6, CSK and LNK negatively regulate FLT3 signaling [3,4,5,6,7,8,9]. Identification of novel interacting proteins will enhance our understanding of FLT3 downstream signaling and will provide an alternative approach to development of therapy
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