An overview of the molecular and clinical significance of the angiopoietin system in leukemia

References

• Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2022;70(1):7–30.
   Web of Science ®Google Scholar
• Beghi E, Logroscino G. editors. Tumors in adolescents and young adults. Karger Medical and Scientific Publishers; 2016.
   Google Scholar
• Hao T, Li-Talley M, Buck A, et al. An emerging trend of rapid increase of leukemia but not all cancers in the aging population in the United States. Sci Rep. 2019;9(1):1–13.
   PubMedGoogle Scholar
• Letilovic T, Vrhovac R, Verstovsek S, et al. Role of angiogenesis in chronic lymphocytic leukemia. Cancer. 2006;107(5):925–934.
   PubMed Web of Science ®Google Scholar
• Folkman J. Clinical applications of research on angiogenesis. N Engl J Med. 1995;333(26):1757–1763.
   PubMed Web of Science ®Google Scholar
• Perez-Atayde AR, Sallan SE, Tedrow U, et al. Spectrum of tumor angiogenesis in the bone marrow of children with acute lymphoblastic leukemia. Am J Pathol. 1997;150(3):815.
   PubMed Web of Science ®Google Scholar
• Colmone A, Sipkins DA. Beyond angiogenesis: the role of endothelium in the bone marrow vascular niche. Transl Res. 2008;151(1):1–9.
   PubMed Web of Science ®Google Scholar
• Ucuzian AA, Gassman AA, East AT, et al. Molecular mediators of angiogenesis. J Burn Care Res. 2010;31(1):158–175.
   PubMed Web of Science ®Google Scholar
• Fagiani E, Christofori G. Angiopoietins in angiogenesis. Cancer Lett. 2013;328(1):18–26.
   PubMed Web of Science ®Google Scholar
• Sato TN, Tozawa Y, Deutsch U, et al. Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation. Nature. 1995;376(6535):70–74.
   PubMed Web of Science ®Google Scholar
• Yu Q. The dynamic roles of angiopoietins in tumor angiogenesis. Future Oncol. 2005;1(4):475–484.
   PubMedGoogle Scholar
• Akwii RG, Sajib MS, Zahra FT, et al. Role of angiopoietin-2 in vascular physiology and pathophysiology. Cells. 2019;8(5):471.
   PubMed Web of Science ®Google Scholar
• Müller A, Lange K, Gaiser T, et al. Expression of angiopoietin-1 and its receptor TEK in hematopoietic cells from patients with myeloid leukemia. Leuk Res. 2002;26(2):163–168.
   PubMed Web of Science ®Google Scholar
• Hou H-A, Chou W-C, Lin L-I, et al. Expression of angiopoietins and vascular endothelial growth factors and their clinical significance in acute myeloid leukemia. Leuk Res. 2008;32(6):904–912.
   PubMed Web of Science ®Google Scholar
• Maffei R, Martinelli S, Castelli I, et al. Increased angiogenesis induced by chronic lymphocytic leukemia B cells is mediated by leukemia-derived Ang2 and VEGF. Leuk Res. 2010;34(3):312–321.
   PubMed Web of Science ®Google Scholar
• Conway EM, Collen D, Carmeliet P. Molecular mechanisms of blood vessel growth. Cardiovasc Res. 2001;49(3):507–521.
   PubMed Web of Science ®Google Scholar
• Folkman J. Angiogenesis-dependent diseases. Seminars in Oncology. 2001; Elsevier.
   PubMed Web of Science ®Google Scholar
• Han Y, Wang X, Wang B, et al. The progress of angiogenic factors in the development of leukemias. Intractable Rare Dis Res. 2016;5(1):6–16.
   PubMed Web of Science ®Google Scholar
• Yancopoulos GD, Davis S, Gale NW, et al. Vascular-specific growth factors and blood vessel formation. Nature. 2000;407(6801):242–248.
   PubMed Web of Science ®Google Scholar
• Moonesi M, Zaka Khosravi S, Molaei Ramshe S, et al. IGF family effects on development, stability, and treatment of hematological malignancies. J Cell Physiol. 2021;236(6):4097–4105.
   PubMed Web of Science ®Google Scholar
• Ghaffari S, Torabi-Rahvar M, Aghayan S, et al. Optimizing interleukin-2 concentration, seeding density and bead-to-cell ratio of T-cell expansion for adoptive immunotherapy. BMC Immunol. 2021;22(1):43.
   PubMed Web of Science ®Google Scholar
• Presta M, Dell’Era P, Mitola S, et al. Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis. Cytokine Growth Factor Rev. 2005;16(2):159–178.
   PubMed Web of Science ®Google Scholar
• Nakashio A, Fujita N, Tsuruo T. Topotecan inhibits VEGF- and bFGF-induced vascular endothelial cell migration via downregulation of the PI3K‐Akt signaling pathway. Int J Cancer. 2002;98(1):36–41.
   PubMed Web of Science ®Google Scholar
• Yayon A, Klagsbrun M, Esko JD, et al. Cell surface, heparin-like molecules are required for binding of basic fibroblast growth factor to its high affinity receptor. Cell. 1991;64(4):841–848.
   PubMed Web of Science ®Google Scholar
• Bieker R, Padró T, Kramer J, et al. Overexpression of basic fibroblast growth factor and autocrine stimulation in acute myeloid leukemia. Cancer Res. 2003;63(21):7241–7246.
   PubMed Web of Science ®Google Scholar
• Krejčí P, Dvořáková D, Krahulcova E, et al. FGF-2 abnormalities in B cell chronic lymphocytic and chronic myeloid leukemias. Leukemia. 2001;15(2):228–237.
   PubMed Web of Science ®Google Scholar
• Partanen J, Armstrong E, Mäkelä T, et al. A novel endothelial cell surface receptor tyrosine kinase with extracellular epidermal growth factor homology domains. Mol Cell Biol. 1992;12(4):1698–1707.
   PubMed Web of Science ®Google Scholar
• Davis S, Aldrich TH, Jones PF, et al. Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. Cell. 1996;87(7):1161–1169.
   PubMed Web of Science ®Google Scholar
• Maisonpierre PC, Suri C, Jones PF, et al. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science. 1997;277(5322):55–60.
   PubMed Web of Science ®Google Scholar
• Korhonen EA, Lampinen A, Giri H, et al. Tie1 controls angiopoietin function in vascular remodeling and inflammation. J Clin Invest. 2016;126(9):3495–3510.
   PubMed Web of Science ®Google Scholar
• Saharinen P, Kerkelä K, Ekman N, et al. Multiple angiopoietin recombinant proteins activate the Tie1 receptor tyrosine kinase and promote its interaction with Tie2. J Cell Biol. 2005;169(2):239–243.
   PubMed Web of Science ®Google Scholar
• Lee HJ, Cho C-H, Hwang S-J, et al. Biological characterization of angiopoietin-3 and angiopoietin-4. FASEB J. 2004;18(11):1200–1208.
   PubMed Web of Science ®Google Scholar
• Park YS, Kim NH, Jo I. Hypoxia and vascular endothelial growth factor acutely up-regulate angiopoietin-1 and Tie2 mRNA in bovine retinal pericytes. Microvasc Res. 2003;65(2):125–131.
   PubMed Web of Science ®Google Scholar
• Nishishita T, Lin PC. Angiopoietin 1, PDGF‐B, and TGF‐β gene regulation in endothelial cell and smooth muscle cell interaction. J Cell Biochem. 2004;91(3):584–593.
   PubMed Web of Science ®Google Scholar
• Procopio WN, Pelavin PI, Lee WM, et al. Angiopoietin-1 and -2 coiled coil domains mediate distinct homo-oligomerization patterns, but fibrinogen-like domains mediate ligand activity. J Biol Chem. 1999;274(42):30196–30201.
   PubMed Web of Science ®Google Scholar
• Kim K-T, Choi H-H, Steinmetz MO, et al. Oligomerization and multimerization are critical for angiopoietin-1 to bind and phosphorylate Tie2. J Biol Chem. 2005;280(20):20126–20131.
   PubMed Web of Science ®Google Scholar
• Harfouche R, Hasséssian HM, Guo Y, et al. Mechanisms which mediate the antiapoptotic effects of angiopoietin-1 on endothelial cells. Microvasc Res. 2002;64(1):135–147.
   PubMed Web of Science ®Google Scholar
• Khan AA, Sandhya VK, Singh P, et al. Signaling network map of endothelial TEK tyrosine kinase. J Signal Transduct. 2014;2014:1–6.
   Google Scholar
• Fukuhara S, Sako K, Minami T, et al. Differential function of Tie2 at cell–cell contacts and cell–substratum contacts regulated by angiopoietin-1. Nat Cell Biol. 2008;10(5):513–526.
   PubMed Web of Science ®Google Scholar
• Arai F, Hirao A, Ohmura M, et al. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell. 2004;118(2):149–161.
   PubMed Web of Science ®Google Scholar
• Papapetropoulos A, Fulton D, Mahboubi K, et al. Angiopoietin-1 inhibits endothelial cell apoptosis via the Akt/survivin pathway. J Biol Chem. 2000;275(13):9102–9105.
   PubMed Web of Science ®Google Scholar
• Aguayo A, Manshouri T, O'Brien S, et al. Clinical relevance of Flt1 and Tie1 angiogenesis receptors expression in B-cell chronic lymphocytic leukemia (CLL). Leuk Res. 2001;25(4):279–285.
   PubMed Web of Science ®Google Scholar
• Verstovsek S, Estey E, Manshouri T, et al. High expression of the receptor tyrosine kinase Tie-1 in acute myeloid leukemia and myelodysplastic syndrome. Leuk Lymphoma. 2001;42(3):511–516.
   PubMed Web of Science ®Google Scholar
• Verstovsek S, Kantarjian H, Manshouri T, et al. Prognostic significance of Tie‐1 protein expression in patients with early chronic phase chronic myeloid leukemia. Cancer. 2002;94(5):1517–1521.
   PubMed Web of Science ®Google Scholar
• Loges S, Heil G, Bruweleit M, et al. Analysis of concerted expression of angiogenic growth factors in acute myeloid leukemia: expression of angiopoietin-2 represents an independent prognostic factor for overall survival. J Clin Oncol. 2005;23(6):1109–1117.
   PubMed Web of Science ®Google Scholar
• Schliemann C, Bieker R, Padro T, et al. Expression of angiopoietins and their receptor Tie2 in the bone marrow of patients with acute myeloid leukemia. Haematologica. 2006;91(9):1203–1211.
   PubMed Web of Science ®Google Scholar
• Quartarone E, Alonci A, Allegra A, et al. Differential levels of soluble angiopoietin‐2 and tie‐2 in patients with haematological malignancies. Eur J Haematol. 2006;77(6):480–485.
   PubMed Web of Science ®Google Scholar
• Lee C, Tien H-F, Hu C, et al. Marrow angiogenesis-associated factors as prognostic biomarkers in patients with acute myelogenous leukaemia. Br J Cancer. 2007;97(7):877–882.
   PubMed Web of Science ®Google Scholar
• Schliemann C, Bieker R, Thoennissen N, et al. Circulating angiopoietin-2 is a strong prognostic factor in acute myeloid leukemia. Leukemia. 2007;21(9):1901–1906.
   PubMed Web of Science ®Google Scholar
• Kümpers P, Koenecke C, Hecker H, et al. Angiopoietin-2 predicts disease-free survival after allogeneic stem cell transplantation in patients with high-risk myeloid malignancies. Blood. 2008;112(5):2139–2148.
   PubMed Web of Science ®Google Scholar
• Hatfield K, Hovland R, Øyan A, et al. Release of angiopoietin-1 by primary human acute myelogenous leukemia cells is associated with mutations of nucleophosmin, increased by bone marrow stromal cells and possibly antagonized by high systemic angiopoietin-2 levels. Leukemia. 2008;22(2):287–293.
   PubMed Web of Science ®Google Scholar
• Aref S, El Menshawy N, Azmy E, et al. Soluble angiopoietin-2/sTie2 receptor ratio is an independent prognostic marker in adult acute myeloid leukemia. Indian J Hematol Blood Transfus. 2009;25(1):17–22.
   PubMed Web of Science ®Google Scholar
• Koenecke C, Kümpers P, Lukasz A, et al. Shedding of the endothelial receptor tyrosine kinase Tie2 correlates with leukemic blast burden and outcome after allogeneic hematopoietic stem cell transplantation for AML. Ann Hematol. 2010;89(5):459–467.
   PubMed Web of Science ®Google Scholar
• Cheng C, Hou H, Jhuang J, et al. High bone marrow angiopoietin-1 expression is an independent poor prognostic factor for survival in patients with myelodysplastic syndromes. Br J Cancer. 2011;105(7):975–982.
   PubMed Web of Science ®Google Scholar
• Atesoglu EB, Tarkun P, Mehtap O, et al. Serum angiopoietin levels are different in acute and chronic myeloid neoplasms: angiopoietins do not only regulate tumor angiogenesis. Indian J Hematol Blood Transfus. 2016;32(2):162–167.
   PubMed Web of Science ®Google Scholar
• Karakurt N, Aksu T, Koksal Y, et al. Angiopoietins in the bone marrow microenvironment of acute lymphoblastic leukemia. Hematology. 2016;21(6):325–331.
   PubMed Web of Science ®Google Scholar
• Desbourdes L, Javary J, Charbonnier T, et al. Alteration analysis of bone marrow mesenchymal stromal cells from de novo acute myeloid leukemia patients at diagnosis. Stem Cells Dev. 2017;26(10):709–722.
   PubMed Web of Science ®Google Scholar
• Handschuh L, Kaźmierczak M, Milewski MC, et al. Gene expression profiling of acute myeloid leukemia samples from adult patients with AML-M1 and -M2 through boutique microarrays, real-time PCR and droplet digital PCR. Int J Oncol. 2018;52(3):656–678.
   PubMed Web of Science ®Google Scholar
• Elwafa RA, Gamaleldin M, Ghallab O. The clinical and prognostic significance of FIS1, SPI1, PDCD7 and Ang2 expression levels in acute myeloid leukemia. Cancer Genet. 2019;233–234:84–95.
   PubMed Web of Science ®Google Scholar
• Khosravi SZ, Ramshe SM, Farsani MA, et al. Investigating the expression pattern of the angiopoietin–Tie system in ALL and its correlation with baseline characteristics. Blood Res. 2021;56(2):79–85.
   PubMed Web of Science ®Google Scholar
• Ichihara E, Kaneda K, Saito Y, et al. Angiopoietin1 contributes to the maintenance of cell quiescence in EVI1high leukemia cells. Biochem Biophys Res Commun. 2011;416(3-4):239–245.
   PubMed Web of Science ®Google Scholar
• Döhner K, Schlenk RF, Habdank M, et al. Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations. Blood. 2005;106(12):3740–3746.
   PubMed Web of Science ®Google Scholar
• Pichiule P, Chavez JC, LaManna JC. Hypoxic regulation of angiopoietin-2 expression in endothelial cells. J Biol Chem. 2004;279(13):12171–12180.
   PubMed Web of Science ®Google Scholar
• Gomei Y, Nakamura Y, Yoshihara H, et al. Functional differences between two Tie2 ligands, angiopoietin-1 and -2, in regulation of adult bone marrow hematopoietic stem cells. Exp Hematol. 2010;38(2):82–89.e1.
   PubMed Web of Science ®Google Scholar
• Hanahan D. Signaling vascular morphogenesis and maintenance. Science. 1997;277(5322):48–50.
   PubMed Web of Science ®Google Scholar
• Kim I, Kim J-H, Moon S-O, et al. Angiopoietin-2 at high concentration can enhance endothelial cell survival through the phosphatidylinositol 3′-kinase/akt signal transduction pathway. Oncogene. 2000;19(39):4549–4552.
   PubMed Web of Science ®Google Scholar
• Felcht M, Luck R, Schering A, et al. Angiopoietin-2 differentially regulates angiogenesis through TIE2 and integrin signaling. J Clin Invest. 2012;122(6):1991–2005.
   PubMed Web of Science ®Google Scholar
• Eklund L, Olsen BR. Tie receptors and their angiopoietin ligands are context-dependent regulators of vascular remodeling. Exp Cell Res. 2006;312(5):630–641.
   PubMed Web of Science ®Google Scholar
• Martinelli S, Maffei R, Castelli I, et al. Increased expression of angiopoietin-2 characterizes early B-cell chronic lymphocytic leukemia with poor prognosis. Leuk Res. 2008;32(4):593–597.
   PubMed Web of Science ®Google Scholar
• Maffei R, Marasca R, Martinelli S, et al. Angiopoietin-2 expression in B-cell chronic lymphocytic leukemia: association with clinical outcome and immunoglobulin heavy-chain mutational status. Leukemia. 2007;21(6):1312–1315.
   PubMed Web of Science ®Google Scholar
• Hüttmann A, Klein-Hitpass L, Thomale J, et al. Gene expression signatures separate B-cell chronic lymphocytic leukaemia prognostic subgroups defined by ZAP-70 and CD38 expression status. Leukemia. 2006;20(10):1774–1782.
   PubMed Web of Science ®Google Scholar
• Kopparapu PK, Miranda C, Fogelstrand L, et al. MCPH1 maintains long‐term epigenetic silencing of ANGPT2 in chronic lymphocytic leukemia. FEBS J. 2015;282(10):1939–1952.
   PubMed Web of Science ®Google Scholar
• Martinelli S, Kanduri M, Maffei R, et al. ANGPT2 promoter methylation is strongly associated with gene expression and prognosis in chronic lymphocytic leukemia. Epigenetics. 2013;8(7):720–729.
   PubMed Web of Science ®Google Scholar
• Vrbacky F, Nekvindova J, Rezacova V, et al. Prognostic relevance of angiopoietin-2, fibroblast growth factor-2 and endoglin mRNA expressions in chronic lymphocytic leukemia. Neoplasma. 2014;61(5):585–592.
   PubMed Web of Science ®Google Scholar
• Maffei R, Martinelli S, Santachiara R, et al. Angiopoietin-2 plasma dosage predicts time to first treatment and overall survival in chronic lymphocytic leukemia. Blood. 2010;116(4):584–592.
   PubMed Web of Science ®Google Scholar
• Vrbacky F, Smolej L, Vroblova V, et al. Angiopoietin-2 mRNA expression is increased in chronic lymphocytic leukemia patients with poor prognostic features. Hematology. 2010;15(4):210–214.
   PubMed Web of Science ®Google Scholar
• Hintsala E, Bono P, Andersson S, et al. Quantification of plasma and bone marrow VEGF and angiopoietin-2 levels in pediatric malignancies. J Pediatr Hematol Oncol. 2012;34(7):503–510.
   PubMed Web of Science ®Google Scholar
• Sato A, Iwama A, Takakura N, et al. Characterization of TEK receptor tyrosine kinase and its ligands, angiopoietins, in human hematopoietic progenitor cells. Int Immunol. 1998;10(8):1217–1227.
   PubMed Web of Science ®Google Scholar
• Bühring HJ, Seiffert M, Bock TA, et al. Expression of novel surface antigens on early hematopoietic cells. Ann N Y Acad Sci. 1999;872(1):25–39.
   PubMedGoogle Scholar
• Yuan HT, Khankin EV, Karumanchi SA, et al. Angiopoietin 2 is a partial agonist/antagonist of Tie2 signaling in the endothelium. Mol Cell Biol. 2009;29(8):2011–2022.
   PubMed Web of Science ®Google Scholar
• Reusch P, Barleon B, Weindel K, et al. Identification of a soluble form of the angiopoietin receptor TIE-2 released from endothelial cells and present in human blood. Angiogenesis. 2001;4(2):123–131.
   PubMedGoogle Scholar
• Valenzuela DM, Griffiths JA, Rojas J, et al. Angiopoietins 3 and 4: diverging gene counterparts in mice and humans. Proc Natl Acad Sci U S A. 1999;96(5):1904–1909.
   PubMed Web of Science ®Google Scholar
• Yamakawa M, Liu LX, Date T, et al. Hypoxia-inducible factor-1 mediates activation of cultured vascular endothelial cells by inducing multiple angiogenic factors. Circ Res. 2003;93(7):664–673.
   PubMed Web of Science ®Google Scholar
• Kesler CT, Pereira ER, Cui CH, et al. Angiopoietin-4 increases permeability of blood vessels and promotes lymphatic dilation. FASEB J. 2015;29(9):3668–3677.
   PubMed Web of Science ®Google Scholar
• Lyu T, Jia N, Wang J, et al. Expression and epigenetic regulation of angiogenesis-related factors during dormancy and recurrent growth of ovarian carcinoma. Epigenetics. 2013;8(12):1330–1346.
   PubMed Web of Science ®Google Scholar
• Andersen S, Donnem T, Al-Shibli K, et al. Prognostic impacts of angiopoietins in NSCLC tumor cells and stroma: VEGF-A impact is strongly associated with ang-2. PLOS One. 2011;6(5):e19773.
   PubMed Web of Science ®Google Scholar
• Seegar TC, Eller B, Tzvetkova-Robev D, et al. Tie1–Tie2 interactions mediate functional differences between angiopoietin ligands. Mol Cell. 2010;37(5):643–655.
   PubMed Web of Science ®Google Scholar
• Xu M, Xu H-H, Lin Y, et al. LECT2, a ligand for Tie1, plays a crucial role in liver fibrogenesis. Cell. 2019;178(6):1478–1492.e20.
   PubMed Web of Science ®Google Scholar
• Marron MB, Singh H, Tahir TA, et al. Regulated proteolytic processing of Tie1 modulates ligand responsiveness of the receptor-tyrosine kinase Tie2. J Biol Chem. 2007;282(42):30509–30517.
   PubMed Web of Science ®Google Scholar
• Savant S, La Porta S, Budnik A, et al. The orphan receptor Tie1 controls angiogenesis and vascular remodeling by differentially regulating Tie2 in tip and stalk cells. Cell Rep. 2015;12(11):1761–1773.
   PubMed Web of Science ®Google Scholar
• Milner CS, Hansen TM, Singh H, et al. Roles of the receptor tyrosine kinases Tie1 and Tie2 in mediating the effects of angiopoietin-1 on endothelial permeability and apoptosis. Microvasc Res. 2009;77(2):187–191.
   PubMed Web of Science ®Google Scholar
• La Porta S, Roth L, Singhal M, et al. Endothelial Tie1-mediated angiogenesis and vascular abnormalization promote tumor progression and metastasis. J Clin Invest. 2018;128(2):834–845.
   PubMed Web of Science ®Google Scholar
• D'Amico G, Korhonen EA, Anisimov A, et al. Tie1 deletion inhibits tumor growth and improves angiopoietin antagonist therapy. J Clin Invest. 2014;124(2):824–834.
   PubMed Web of Science ®Google Scholar
• Hansen TM, Singh H, Tahir TA, et al. Effects of angiopoietins-1 and -2 on the receptor tyrosine kinase Tie2 are differentially regulated at the endothelial cell surface. Cell Signal. 2010;22(3):527–532.
   PubMed Web of Science ®Google Scholar
• Zhang Y, Kontos CD, Annex BH, et al. Angiopoietin–Tie signaling pathway in endothelial cells: a computational model. iScience. 2019;20:497–511.
   PubMed Web of Science ®Google Scholar
• Kivivuori SM, Siitonen S, Porkka K, et al. Expression of vascular endothelial growth factor receptor 3 and Tie1 tyrosine kinase receptor on acute leukemia cells. Pediatr Blood Cancer. 2007;48(4):387–392.
   PubMed Web of Science ®Google Scholar
• Oliner J, Min H, Leal J, et al. Suppression of angiogenesis and tumor growth by selective inhibition of angiopoietin-2. Cancer Cell. 2004;6(5):507–516.
   PubMed Web of Science ®Google Scholar
• Mazzieri R, Pucci F, Moi D, et al. Targeting the ANG2/TIE2 axis inhibits tumor growth and metastasis by impairing angiogenesis and disabling rebounds of proangiogenic myeloid cells. Cancer Cell. 2011;19(4):512–526.
   PubMed Web of Science ®Google Scholar
• Reikvam H, Hatfield KJ, Lassalle P, et al. Targeting the angiopoietin (Ang)/Tie-2 pathway in the crosstalk between acute myeloid leukaemia and endothelial cells: studies of Tie-2 blocking antibodies, exogenous Ang-2 and inhibition of constitutive agonistic Ang-1 release. Expert Opin Investig Drugs. 2010;19(2):169–183.
   PubMed Web of Science ®Google Scholar
• Bachegowda L, Morrone K, Winski SL, et al. Pexmetinib: a novel dual inhibitor of Tie2 and p38 MAPK with efficacy in preclinical models of myelodysplastic syndromes and acute myeloid leukemia. Cancer Res. 2016;76(16):4841–4849.
   PubMed Web of Science ®Google Scholar
• Hadzijusufovic E, Albrecht-Schgoer K, Huber K, et al. Nilotinib-induced vasculopathy: identification of vascular endothelial cells as a primary target site. Leukemia. 2017;31(11):2388–2397.
   PubMed Web of Science ®Google Scholar
• Ma D, Liu P, Hu C, et al. Intracellular angiopoietin-1 promotes TKI-resistance via activation of JAK/STAT5 pathway in chronic myeloid leukemia. Oncogene. 2023;42(2):124–137.
   PubMed Web of Science ®Google Scholar