EphA2 Is a Therapy Target in EphA2-Positive Leukemias but Is Not Essential for Normal Hematopoiesis or Leukemia

Abstract

Members of the Eph family of receptor tyrosine kinases and their membrane bound ephrin ligands have been shown to play critical roles in many developmental processes and more recently have been implicated in both normal and pathological processes in post-embryonic tissues. In particular, expression studies of Eph receptors and limited functional studies have demonstrated a role for the Eph/ephrin system in hematopoiesis and leukemogenesis. In particular, EphA2 was reported on hematopoietic stem cells and stromal cells. There are also reports of EphA2 expression in many different types of malignancies including leukemia, however there is a lack of knowledge in understanding the role of EphA2 in hematopoiesis and leukemogenesis. We explored the role of EphA2 in hematopoiesis by analyzing wild type and EphA2 knockout mice. Mature, differentiated cells, progenitors and hematopoietic stem cells derived from knockout and control mice were analyzed and no significant abnormality was detected. These studies showed that EphA2 does not have an obligatory role in normal hematopoiesis. Comparative studies using EphA2-negative MLL-AF9 leukemias derived from EphA2-knockout animals showed that there was no detectable functional role for EphA2 in the initiation or progression of the leukemic process. However, expression of EphA2 in leukemias initiated by MLL-AF9 suggested that this protein might be a possible therapy target in this type of leukemia. We showed that treatment with EphA2 monoclonal antibody IF7 alone had no effect on tumorigenicity and latency of the MLL-AF9 leukemias, while targeting of EphA2 using EphA2 monoclonal antibody with a radioactive payload significantly impaired the leukemic process. Altogether, these results identify EphA2 as a potential radio-therapeutic target in leukemias with MLL translocation.

EphA3 as a target for antibody immunotherapy in acute lymphoblastic leukemia

“…27 We showed that EphA3 was expressed in~1/3 of ALL cases and appears to be more significantly expressed in some subgroups, particularly cases having the t(1; 19) translocation. Although only four cases with MLL translocations were tested, taken together with our previous data, 28 it seems unlikely that EphA3 would be expressed in these leukemias as MLL transcriptionally induces expression of other Eph receptors with redundant function. Therapy with anti-EphA3 antibody was investigated using xenografts of the EphA3-positive (LK63, Reh/ A3) and the EphA3-negative/low (Reh, LK63/A3KD) cell lines.…”

Pharmacological targeting of the ephrin receptor kinase signalling by GLPG1790 in vitro and in vivo reverts oncophenotype, induces myogenic differentiation and radiosensitizes embryonal rhabdomyosarcoma cells

“…GLPG1790 is a selective and potent pan-inhibitor of the EPH receptors [21], which are overexpressed in many malignancies [12][13][14][15][16] and which are often associated with a poor clinical outcome [13] as well as with a resistance to chemo- [31,32] and radio-therapy [33][34][35]. The present study has investigated, for the first time, the possible in vitro antitumour activity of GLPG1790 in ERMS by dissecting the drug-mediated biological effects and molecular mechanisms in RD and TE671 human ERMS cell lines.…”

“…GLPG1790 inhibits EPH receptor activity and blocks both forward and revers Ephrin signals which, synergistically or individually, support (i) activation of AKT/mTOR and MEK/ERK signalling that support proliferation and cancer stem cell phenotype; (ii) inhibition of pro-apoptotic signal mediated by JNKs; (iii) pro-differentiating signal sustained by p38; (iv) activation of damaged DNA repair molecular mechanisms; (v) motility and invasion abilities by sustaining the SRC-mediated integrin signals than 90%, altering the accumulation of DNA DSBs, as confirmed by the impaired expression of the phosphorylated form of the H2AX histone [48]. Even if the relationship between EPH/Ephrin signalling, DSB repair machinery and response to RT is still largely unknown; a correlation between EPH overexpression and the acquisition of a radioresistant phenotype has been reported in other solid tumours [34,35,49,50]. Here, we showed that GLPG1790 abrogates the RT-induced ATM and DNA-PKcs phosphorylation, whose activation is linked to the HR and NHEJ pathways, respectively [47].…”

Chronic TCDD exposure results in the dysregulation of gene expression in splenic B-lymphocytes and in the impairments in T-cell and B-cell differentiation in mouse model

“…Indeed, Eph receptor tyrosine kinase Ephrin A receptor proto-oncogene Eph2A was the top induced transcript in our dataset (Log2 = 10.41). Eph2A is overexpressed in most cancer types and specifically involved in B-cell leukemia (Charmsaz et al, 2015;Trinidad et al, 2009). Hypermethylation of EphA2 was detected in leukemia cell lines (Kuang et al, 2010).…”