EPH/Ephrin Signaling in Normal Hematopoiesis and Hematologic Malignancies: Deciphering Their Intricate Role and Unraveling Possible New Therapeutic Targets
Abstract
:Simple Summary
Abstract
1. Introduction
2. Ephrins and EPHs: Structure and Signaling Pathways
3. EPH/Ephrin Expression in Hematopoiesis
3.1. Hematopoietic Stem and Progenitor Cells
3.2. Erythropoiesis
3.3. Lymphopoiesis
3.4. Other Hematopoietic and Immune Cells
4. EPH/Ephrin Expression in the Setting of Hematologic Neoplasia
4.1. EPH/Ephrin Expression in Leukemia/Lymphoma Cell Lines
4.2. EPH/Ephrin Expression in Hematologic Malignancies
4.2.1. Leukemias of Myeloid Origin
4.2.2. Leukemias of Lymphoid Origin
4.2.3. Lymphomas
4.2.4. Multiple Myeloma (MM)
5. EPH/Ephrin Therapeutic Targeting in Hematologic Malignancies
6. Discussion
7. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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EPHA1 | Human CD34+ HSCs [86,87] Rat T lymphocytes—during thymic development [88] |
EPHA2 | Human CD34+ HSCs [89] Human CD133+ HSCs [89] Mouse Lin-ckit + sca1+ HSCs [90] Rat T lymphocytes—during thymic development [88] |
EPHA3 | Mouse Lin-ckit + sca1+ HSCs [90] Rat T lymphocytes—during thymic development [88] |
EPHA4 | Human platelets [91,92] Rat T lymphocytes—during thymic development [88] Human pro- and pre-B cells [93] |
EPHA6 | Mouse Lin-ckit + sca1+ HSCs [90] |
EPHA7 | Rat T lymphocytes—during thymic development [88] Human pro- and pre-B cells [93] Normal lymphocytes [94] |
EPHA8 | Mouse Lin-ckit + sca1+ HSCs [90] |
EPHB1 | Human platelets [92] |
EPHB2 | Human CD133+ HSCs [89] Human CD34+ HSCs—partially expressed [89] |
EPHB4 | Bone marrow CD34+ cells [95] Erythroid progenitor cells [96] HSPCs [97] |
EPHB6 | Mouse thymic T cells [98] |
EphrinA1 | Rat T lymphocytes—during thymic development [88] |
EphrinA3 | Human CD34+ HSPCs [87] Rat T lymphocytes—during thymic development [88] |
EphrinA4 | Human CD34+ HSPCs [87] Mouse Lin-ckit + sca1+ HSCs [90] |
EphrinA5 | Mouse Lin-ckit + sca1+ HSCs [90] Rat T lymphocytes—during thymic development [88] |
EphrinB1 | Human platelets [92] Mouse T lymphocytes—during thymic development [99] |
Leukemia/Lymphoma Cell Lines | Hematologic Malignancies | |
---|---|---|
EPHA2 | ALL: EPHA2 hypermethylation [131] | |
EPHA3 | LK63 pre-B ALL cell line [132] T-cell leukemia cell lines (Jurkat, JM, HSB-2) [133] EPHA3 identified as a CD28-responsive gene in Jurkat cells [134] | Mouse model of CML blast crisis: EPHA3 identified as a common CRG [135] AML: EPHA3 CNVs [136,137] ALL: EPHA3 CNVs [136] CLL: EPHA3 CNVs [136] CML: EPHA3 CNVs [136] MDS: EPHA3 CNVs [136] MM: EPHA3 highly expressed in endothelial BM cells [138] |
EPHA4 | ALL: EPHA4 hypermethylation [131] | |
EPHA5 | ALL: EPHA5 hypermethylation [131] | |
EPHA6 | ALL: EPHA6 hypermethylation [131] | |
EPHA7 | Leukemic cell lines with ALL1 gene translocations: transcriptional up-regulation of the EPHA7 [139] | ALL: EPHA7 hypermethylation [131] T-ALL/lymphoma with 6q deletion: EPHA7 as a tumor suppressor [140] GC B cell NHL: EPHA7 hypermethylation and repression [94] FL: EPHA7 proposed as a tumor suppressor [141] |
EPHA10 | ALL: EPHA10 hypermethylation [131] | |
EPHB1 | pediatric AML: decreased EPHB1 peptide phosphorylation and mRNA expression compared to healthy controls, hypermethylation of the EPHB1 promoter [142] ALL: EPHB1 hypermethylation [131] | |
EPHB2 | ALL: EPHB2 hypermethylation [131] | |
EPHB3 | T-ALL cell lines H9 and E6.1 [73] | ALL: EPHB3 hypermethylation [131] |
EPHB4 | Human leukemia/lymphoma cell lines: EPHB4 mRNA expression in 68 of the 70 studied cell lines [143] K562-R cell line (human imatinib-resistant CML cell line): EPHB4 overexpression [144] Philadelphia chromosome-positive ALL cell lines: imatinib resistance mediated by EPHB4 activation [145] | AML: 28% (7/25) of newly diagnosed AML BM samples over-expressed EPHB4 protein [146] CML: EPHB4 mRNA levels in BM cells significantly increased according to clinical stages (increased EPHB4 expression in blast crisis compared to chronic phase) [144] Childhood ALL: prevalent methylation of the EPHB4 [147] ALL: EPHB4 hypermethylation [131] PTLDs: EPHB4 expression suppressed in EBV+ PTLDs [148] |
EPHB6 | T-ALL cell lines H9 and E6.1 [73] | AML: Increased EPHB6 expression [149] T-cell leukemia/lymphoma: increased EPHB6 expression [150,151] T-ALL: EPHB6 expression confers increased sensitivity to doxorubicin [151] CLL: EPHB6 expression correlated with a high content of ZAP-70 mRNA and a poor prognosis [152] |
EphrinA1 | ALL: EFNA1 hypermethylation [131] | |
EphrinA3 | ALL: EFNA3 hypermethylation [131] | |
EphrinA4 | CLL: High serum levels of a soluble ephrinA4 isoform positively correlated with increasing PB lymphocyte counts and lymphadenopathy [152] CLL: ephrinA4 expression on PB CLL cells inversely correlated with lymphadenopathy [153] | |
EphrinA5 | ALL: EFNA5 hypermethylation [131] | |
EphrinB1 | Jurkat cells: EphrinB1 enhanced their metastatic potential [154] | Pediatric B precursor ALL: EFNB1 identified among downregulated DEGs [155] B-ALL: EFNB1 as an independent prognostic factor for B-ALL; EFNB1 mRNA levels significantly lower in B-ALL patients compared to controls [155] ALL: EFNB1 hypermethylation [131] |
EphrinB2 | Human leukemia/lymphoma cell lines: EphrinB2 mRNA expression in 58 of the 70 studied cell lines [143] Erythroid leukemia-derived cell line: Induction of proliferation and colony formation, upregulation of growth-related gene expression [156] | ALL: EFNB2 hypermethylation [131] |
Target | Type of Hematologic Malignancy | Drug | Type of Study | Outcome | Reference |
---|---|---|---|---|---|
EPHA2 | ALL1/AF9 leukemias | EPHA2 mAb (IF7) radiolabeled with Lutetium-177 | Preclinical: Mouse model | Survival advantage | [168] |
EPHA3 | Pre-B-ALL | EPHA3 with α-particle-emitting Bismuth-213 payload | In vitro: EPHA3-expressing leukemic xenografts | Antitumor effect | [169] |
AML, MDS/MPN, MDS, DLBCL, MF | EPHA3 mAb (KB004) | Clinical: phase I | Responses in AML, MF, MDS/MPN, and MDS patients | [170] | |
EPHA7 | Leukemias with ALL1 translocations | ERK inhibitor (indirect EPHA7 signaling inhibition via its downstream target ERK) | In vitro: K562 cells | Induction of apoptotic cell death | [139] |
Lymphomas | EPHA7 delivered by anti-CD20 mAb (Rituximab) | Preclinical: xenografted human lymphomas | Inhibition of ERK and SRC activity; induction of cell death | [141] | |
EPHB4 | Imatinib-resistant CML | Vandetanib | Preclinical: K562 cells | Growth arrest; overcoming of imatinib resistance | [177] |
EPHB4 | AML cases with high EPHB4 expression | EPHB4 mAb (MAb131) | Preclinical: myeloid leukemia cell lines and human myeloid leukemia xenograft models | Effective against AML in vitro and in vivo | [139] |
EphrinB2 | T-ALL | Combination of TPD7 and berberine (TAB) | Preclinical: Jurkat cells | Decrease in the levels and phosphorylation of ephrinB2; downregulation of PDZ domain-interacting proteins (syntenin-1 and PICK1); decreased phosphorylation of VEGFR2; inhibition of Rac1; upregulation of PTEN | [175] |
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Stergiou, I.E.; Papadakos, S.P.; Karyda, A.; Tsitsilonis, O.E.; Dimopoulos, M.-A.; Theocharis, S. EPH/Ephrin Signaling in Normal Hematopoiesis and Hematologic Malignancies: Deciphering Their Intricate Role and Unraveling Possible New Therapeutic Targets. Cancers 2023, 15, 3963. https://doi.org/10.3390/cancers15153963
Stergiou IE, Papadakos SP, Karyda A, Tsitsilonis OE, Dimopoulos M-A, Theocharis S. EPH/Ephrin Signaling in Normal Hematopoiesis and Hematologic Malignancies: Deciphering Their Intricate Role and Unraveling Possible New Therapeutic Targets. Cancers. 2023; 15(15):3963. https://doi.org/10.3390/cancers15153963
Chicago/Turabian StyleStergiou, Ioanna E., Stavros P. Papadakos, Anna Karyda, Ourania E. Tsitsilonis, Meletios-Athanasios Dimopoulos, and Stamatios Theocharis. 2023. "EPH/Ephrin Signaling in Normal Hematopoiesis and Hematologic Malignancies: Deciphering Their Intricate Role and Unraveling Possible New Therapeutic Targets" Cancers 15, no. 15: 3963. https://doi.org/10.3390/cancers15153963