Association of the EGF-TM7 receptor CD97 expression with FLT3-ITD in acute myeloid leukemia
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Manja Wobus1, Martin Bornhäuser1,3, Angela Jacobi2, Martin Kräter1, Oliver Otto2, Claudia Ortlepp1, Jochen Guck2, Gerhard Ehninger1, Christian Thiede1, Uta Oelschlägel1
1Division of Hematology, Oncology and Stem Cell Transplantation, Department of Medicine I, University Hospital Carl Gustav Carus, Technische Universität, Dresden, Germany
2Biotechnology Center, Technische Universität Dresden, Dresden, Germany
3German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
Manja Wobus, e-mail: [email protected]
Keywords: AML, CD97, FLT3-ITD, bone marrow microenvironment
Received: July 31, 2015 Accepted: September 25, 2015 Published: October 07, 2015
Internal tandem duplications within the juxtamembrane region of the FMS-like tyrosine kinase receptor FLT3 (FLT3-ITD) represents one of the most common mutations in patients with acute myeloid leukemia (AML) which results in constitutive aberrant activation, increased proliferation of leukemic progenitors and is associated with an aggressive clinical phenotype. The expression of CD97, an EGF-TM7 receptor, has been linked to invasive behavior in thyroid and colorectal cancer. Here, we have investigated the association of CD97 with FLT3-ITD and its functional consequences in AML.
Higher CD97 expression levels have been detected in 208 out of 385 primary AML samples. This was accompanied by a significantly increased bone marrow blast count as well as by mutations in the FLT3 gene. FLT3-ITD expressing cell lines as MV4-11 and MOLM-13 revealed significantly higher CD97 levels than FLT3 wildtype EOL-1, OCI-AML3 and HL-60 cells which were clearly decreased by the tyrosine kinase inhibitors PKC412 and SU5614. CD97 knock down by short hairpin RNA in MV4-11 cells resulted in inhibited trans-well migration towards fetal calf serum (FCS) and lysophosphatidic acid (LPA) being at least in part Rho-A dependent. Moreover, knock down of CD97 led to an altered mechanical phenotype, reduced adhesion to a stromal layer and lower wildtype FLT3 expression.
Our results, thus, constitute the first evidence for the functional relevance of CD97 expression in FLT3-ITD AML cells rendering it a potential new theragnostic target.
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