Association of the EGF-TM7 receptor CD97 expression with FLT3-ITD in acute myeloid leukemia.

Manja Wobus,Uta Oelschlägel,Angela Jacobi,Jochen Guck,Martin Kräter,Oliver Otto,Christian Thiede,Claudia Ortlepp,Gerhard Ehninger,Martin Bornhäuser

doi:10.18632/oncotarget.5661

Manja Wobus, Uta Oelschlägel + Show 8 more

Open Access

https://doi.org/10.18632/oncotarget.5661

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Journal: Oncotarget	Publication Date: Oct 7, 2015
Citations: 39	License type: cc-by

Affiliation: University Hospital Carl Gustav Carus, TU Dresden

Abstract

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.

Highlights

Acute myeloid leukemia (AML) is a heterogeneous group of diseases and the most frequent leukemia subtype in adult patients
We detected significantly higher CD97 expression levels in 208 out of 385 samples compared to bone marrow blasts from healthy donors (n = 10) and MDS patients (n = 15)
CD97 expression tended to be higher in granulocytes and monocytes of MDS samples, no significant differences could be detected in comparison to the expression in blasts (Figure 1D)

Summary

Introduction

Acute myeloid leukemia (AML) is a heterogeneous group of diseases and the most frequent leukemia subtype in adult patients. It is characterized by an increase in the number of malignant myeloid progenitors in the bone marrow and an arrest of their maturation, frequently resulting in hematopoietic insufficiency (granulocytopenia, thrombocytopenia, or anemia), with or without leukocytosis [1]. Mesenchymal stromal cells (MSCs) have been described as a major component of the bone marrow microenvironment. In analogy to their support of early hematopoietic stem and progenitor cells (HSPCs) they have been demonstrated to induce adhesionmediated chemoresistance of clonogenic leukemic cells [2]. Chemotherapy was shown to increase leukemia cell stiffness which occurred before caspase activation and peaked after completion of cell death [5]

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