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

Charmsaz S, Beckett K, Smith FM, Bruedigam C, Moore AS, Al-Ejeh F, Lane SW, Boyd AW - PLoS ONE (2015)

Bottom Line: These studies showed that EphA2 does not have an obligatory role in normal hematopoiesis.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.

View Article: PubMed Central - PubMed

Affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.

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.

No MeSH data available.


Related in: MedlinePlus

MLL-AF9 EphA2 knockout mice have similar leukemogenic potential.(A) Serial MLL-AF9 leukemic transplantation model. (B) Survival of leukemic mice transplanted with EphA2 knockout MLL-AF9–transduced hematopoietic stem cells (LKS+) compared to wild type MLL-AF9–transduced hematopoietic stem cells (LKS+) showed no significant differences between the two groups (n = 4 wild type, n = 3 EphA2 knockout, 2 independent experiments). (C) Percentage of GFP+ cells in bone marrow, spleen and blood of the EphA2 knockout and wild type MLL-AF9 bone marrow, spleen and blood at time of cull did not show any significant differences between the two groups. (D) Survival of secondary MLL-AF9 mice transplanted with GFP+ EphA2 knockout or GFP+ wild type MLL-AF9 cells from the primary transplant showed no significant differences between the two groups (n = 16 wild type, n = 19 EphA2 knockout, 4 independent experiments). (E) Percentage of GFP+ cells in bone marrow, spleen and blood of the secondary transplanted wild type or EphA2 knockout MLL-AF9 mice did not show any significant differences between the two groups. Each dot corresponds to one individual mouse. The data represent the mean ± SEM. Unpaired t test was performed for statistical analyses. The survival is presented as Kaplan-Meier survival curves (Log rank test was used for statistical analysis).
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pone.0130692.g005: MLL-AF9 EphA2 knockout mice have similar leukemogenic potential.(A) Serial MLL-AF9 leukemic transplantation model. (B) Survival of leukemic mice transplanted with EphA2 knockout MLL-AF9–transduced hematopoietic stem cells (LKS+) compared to wild type MLL-AF9–transduced hematopoietic stem cells (LKS+) showed no significant differences between the two groups (n = 4 wild type, n = 3 EphA2 knockout, 2 independent experiments). (C) Percentage of GFP+ cells in bone marrow, spleen and blood of the EphA2 knockout and wild type MLL-AF9 bone marrow, spleen and blood at time of cull did not show any significant differences between the two groups. (D) Survival of secondary MLL-AF9 mice transplanted with GFP+ EphA2 knockout or GFP+ wild type MLL-AF9 cells from the primary transplant showed no significant differences between the two groups (n = 16 wild type, n = 19 EphA2 knockout, 4 independent experiments). (E) Percentage of GFP+ cells in bone marrow, spleen and blood of the secondary transplanted wild type or EphA2 knockout MLL-AF9 mice did not show any significant differences between the two groups. Each dot corresponds to one individual mouse. The data represent the mean ± SEM. Unpaired t test was performed for statistical analyses. The survival is presented as Kaplan-Meier survival curves (Log rank test was used for statistical analysis).

Mentions: The elevated level of EphA2 expression in MLL-AF9 leukemias raised the possibility that this protein may have a role in MLL-AF9 leukemogenesis. To explore this possibility, a series of MLL-AF9 leukemic transplantation experiments were conducted (Fig 5A). Bone marrow cells from C57BL/6 wild type or EphA2 knockout were infected with the MLL-AF9 oncogene and transplanted into C57BL/6 wild type mice. The results from this transplantation showed that lack of EphA2 expression in the donor mice was dispensable for the generation of leukemia (Fig 5B and 5C).


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

Charmsaz S, Beckett K, Smith FM, Bruedigam C, Moore AS, Al-Ejeh F, Lane SW, Boyd AW - PLoS ONE (2015)

MLL-AF9 EphA2 knockout mice have similar leukemogenic potential.(A) Serial MLL-AF9 leukemic transplantation model. (B) Survival of leukemic mice transplanted with EphA2 knockout MLL-AF9–transduced hematopoietic stem cells (LKS+) compared to wild type MLL-AF9–transduced hematopoietic stem cells (LKS+) showed no significant differences between the two groups (n = 4 wild type, n = 3 EphA2 knockout, 2 independent experiments). (C) Percentage of GFP+ cells in bone marrow, spleen and blood of the EphA2 knockout and wild type MLL-AF9 bone marrow, spleen and blood at time of cull did not show any significant differences between the two groups. (D) Survival of secondary MLL-AF9 mice transplanted with GFP+ EphA2 knockout or GFP+ wild type MLL-AF9 cells from the primary transplant showed no significant differences between the two groups (n = 16 wild type, n = 19 EphA2 knockout, 4 independent experiments). (E) Percentage of GFP+ cells in bone marrow, spleen and blood of the secondary transplanted wild type or EphA2 knockout MLL-AF9 mice did not show any significant differences between the two groups. Each dot corresponds to one individual mouse. The data represent the mean ± SEM. Unpaired t test was performed for statistical analyses. The survival is presented as Kaplan-Meier survival curves (Log rank test was used for statistical analysis).
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4470658&req=5

pone.0130692.g005: MLL-AF9 EphA2 knockout mice have similar leukemogenic potential.(A) Serial MLL-AF9 leukemic transplantation model. (B) Survival of leukemic mice transplanted with EphA2 knockout MLL-AF9–transduced hematopoietic stem cells (LKS+) compared to wild type MLL-AF9–transduced hematopoietic stem cells (LKS+) showed no significant differences between the two groups (n = 4 wild type, n = 3 EphA2 knockout, 2 independent experiments). (C) Percentage of GFP+ cells in bone marrow, spleen and blood of the EphA2 knockout and wild type MLL-AF9 bone marrow, spleen and blood at time of cull did not show any significant differences between the two groups. (D) Survival of secondary MLL-AF9 mice transplanted with GFP+ EphA2 knockout or GFP+ wild type MLL-AF9 cells from the primary transplant showed no significant differences between the two groups (n = 16 wild type, n = 19 EphA2 knockout, 4 independent experiments). (E) Percentage of GFP+ cells in bone marrow, spleen and blood of the secondary transplanted wild type or EphA2 knockout MLL-AF9 mice did not show any significant differences between the two groups. Each dot corresponds to one individual mouse. The data represent the mean ± SEM. Unpaired t test was performed for statistical analyses. The survival is presented as Kaplan-Meier survival curves (Log rank test was used for statistical analysis).
Mentions: The elevated level of EphA2 expression in MLL-AF9 leukemias raised the possibility that this protein may have a role in MLL-AF9 leukemogenesis. To explore this possibility, a series of MLL-AF9 leukemic transplantation experiments were conducted (Fig 5A). Bone marrow cells from C57BL/6 wild type or EphA2 knockout were infected with the MLL-AF9 oncogene and transplanted into C57BL/6 wild type mice. The results from this transplantation showed that lack of EphA2 expression in the donor mice was dispensable for the generation of leukemia (Fig 5B and 5C).

Bottom Line: These studies showed that EphA2 does not have an obligatory role in normal hematopoiesis.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.

View Article: PubMed Central - PubMed

Affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.

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.

No MeSH data available.


Related in: MedlinePlus