JCHOR

The Journal of Current Hematology & Oncology Research regularly publishes internationally qualified research in hematology and oncology within the current scholarly knowledge.

EndNote Style
Index
Review
The role of ELABELA in targeted treatment of acute myeloid leukaemia
Acute myeloid leukaemia is a clonal stem cell disease. Various molecular targets are being sought in this disease which has a low chance of cure. However, it is desired that targeted treatments should have few side effects. We tried to understand whether the embryogenic peptide elabela, which has been closely associated with many pathways involved in cancer mechanism, is a peptide worth investigating in targeted treatment of acute myeloid leukaemia.


1. Vago L, Gojo I. Immune escape and immunotherapy of acute myeloid leukemia. J Clin Invest. 2020;130(4):1552-1564. doi:10.1172/JCI129204
2. Gruszka AM, Valli D, Alcalay M. Wnt signalling in acute myeloid leukaemia. Cells. 2019;8(11):1403. doi:10.3390/cells8111403
3. Daver N, Schlenk RF, Russell NH, Levis MJ. Targeting FLT3 mutations in AML: review of current knowledge and evidence. Leukemia. 2019; 33(2):299-312. doi:10.1038/s41375-018-0357-9
4. Molica M, Breccia M, Foa R, Jabbour E, Kadia TM. Maintenance therapy in AML: the past, the present and the future. Am J Hematol. 2019;94(11):1254-1265. doi:10.1002/ajh.25620
5. Kayser S, Levis MJ. Advances in targeted therapy for acute myeloid leukaemia. Br J Haematol. 2018;180(4):484-500. doi:10.1111/bjh.15032
6. Ajani JA, Song S, Hochster HS, Steinberg IB. Cancer stem cells: the promise and the potential. Semin Oncol. 2015;42(Suppl 1): S3-17. doi:10. 1053/j.seminoncol.2015.01.001
7. Yang L, Shi P, Zhao G, et al. Targeting cancer stem cell pathways for cancer therapy. Signal Transduct Target Ther. 2020;5(1):8. doi:10.1038/s41392-020-0110-5
8. Visvader JE, Lindeman GJ. Cancer stem cells: current status and evolving complexities. Cell Stem Cell. 2012;10:717-728. doi:10.1016/j.stem.2012.05.007
9. Lapidot T, Sirard C, Vormoor J, et al. A cell initiating human acute myeloid leukemia after transplantation into SCID mice. Nature. 1994; 367:645-648. doi:10.1038/367645a0
10. Croker AK, Allan AL. Cancer stem cells: implications for the progression and treatment of metastatic disease. J Cell Mol Med. 2008; 12(2):374-390. doi:10.1111/j.1582-4934.2007.00211. x
11. Chng SC, Ho L, Tian J, Reversade B. ELABELA: a hormone essential for heart development signals via the apelin receptor. Dev Cell. 2013;27(6): 672-680. doi:10.1016/j.devcel.2013.11.002
12. Deshwar AR, Chng SC, Ho L, Reversade B, Scott IC. The apelin receptor enhances Nodal/TGFβ signaling to ensure proper cardiac development. Elife. 2016;5:e13758. doi:10.7554/eLife.13758
13. Pauli A, Norris ML, Valen E, et al. Toddler: an embryonic signal that promotes cell movement via apelin receptors. Science. 2014;343(6172): 1248636. doi:10.1126/science.1248636
14. Shin K, Kenward C, Rainey JK. Apelinergic system structure and function. Compr Physiol. 2017;8(1):407-450. doi:10.1002/cphy.c170028
15. Kanwar SS, Yu Y, Nautiyal J, Patel BB, Majumdar AP. The Wnt/beta-catenin pathway regulates growth and maintenance of colonospheres. Mol Cancer. 2010;9:212. doi:10.1186/1476-4598-9-212
16. Li C, Heidt DG, Dalerba P, et al. Identification of pancreatic cancer stem cells.Cancer Res. 2007;67(3):1030-1037. doi:10.1158/0008-5472.CAN-06-2030
17. Wang J, Wakeman TP, Lathia JD, et al. Notch promotes radioresistance of glioma stem cells.Stem Cells. 2010;28(1):17-28. doi:10.1002/stem.261
18. Acik DY, Bankir M, Baylan FA, Aygun B. Can ELABELA be a novel target in the treatment of chronic lymphocytic leukaemia? BMC Cancer. 2019;19(1):1086. doi:10.1186/s12885-019-6325-6
19. Yi Y, Tsai SH, Cheng JC, et al. APELA promotes tumour growth and cell migration in ovarian cancer in a p53-dependent manner. Gynecol Oncol. 2017;147(3):663-671. doi:10.1016/j.ygyno.2017.10.016
20. Ganguly D, Cai C, Sims MM, et al. APELA expression in glioma, and its association with patient survival and tumor grade. Pharmaceuticals (Basel). 2019;12(1):45. doi:10.3390/ph12010045
21. Ho L, Tan SY, Wee S, et al. ELABELA is an endogenous growth factor that sustains hESC self-renewal via the PI3K/AKT pathway. Cell Stem Cell. 2015;17(4):435-447. doi:10.1016/j.stem.2015.08.010
22. Li M, Gou H, Tripathi BK, Huang J. An apela RNA-containing negative feedback loop regulates p53-mediated apoptosis in embryonic stem cells. Cell Stem Cell. 2015;16(6):669-683. doi:10.1016/j.stem.2015.04.002
23. Dick JE. Acute myeloid leukemia stem cells. Ann N Y Acad Sci. 2005; 1044:1-5. doi:10.1196/annals.1349.001
24. Heidel FH, Arreba-Tutusaus P, Armstrong SA, Fischer T. Evolutionarily conserved signaling pathways: acting in the shadows of acute myelogenous leukemia’s genetic diversity. Clin Cancer Res. 2015;21:240-248. doi:10.1158/1078-0432.CCR-14-1436
25. Han Y, Liu D, Li L. PD-1/PD-L1 pathway: current researches in cancer. Am J Cancer Res. 2020;10(3):727-742.
26. Galluzzi L, Spranger S, Fuchs E, López-Soto A. WNT signaling in cancer immunosurveillance. Trends Cell Biol. 2019;29(1):44-65. doi:10. 1016/j.tcb.2018.08.005
27. Lee KH, Li M, Michalowski AM, et al. A genomewide study identifies the Wnt signaling pathway as a major target of p53 in murine embryonic stem cells. Proc Natl Acad Sci USA. 2010;107(1):69-74. doi:10.1073/pnas. 0909734107
28. Mudgapalli N, Nallasamy P, Chava H, et al. The role of exosomes and MYC in therapy resistance of acute myeloid leukemia: challenges and opportunities. Mol Aspects Med. 2019;70:21-32. doi:10.1016/j.mam.2019. 10.001
29. Takam Kamga P, Dal Collo G, Cassaro A, et al. Small molecule inhibitors of microenvironmental Wnt/β-catenin signaling enhance the chemosensitivity of acute myeloid leukemia. Cancers (Basel). 2020; 12(9):2696. doi:10.3390/cancers12092696
30. Wu B, Chien EY, Mol CD, et al. Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists. Science. 2010;330(6007):1066-1071. doi:10.1126/science.1194396
31. Vermeire K, Schols D, Bell TW. Inhibitors of HIV infection via the cellular CD4 receptor. Curr Med Chem. 2006;13(7):731-743. doi:10.2174/ 092986706776055599
32. Chapman NA, Dupré DJ, Rainey JK. The apelin receptor: physiology, pathology, cell signalling, and ligand modulation of a peptide-activated class A GPCR. Biochem Cell Biol. 2014;92(6):431-440. doi:10.1139/bcb-2014-0072
33. Uribesalgo I, Hoffmann D, Zhang Y, et al. Apelin inhibition prevents resistance and metastasis associated with anti-angiogenic therapy. EMBO Mol Med. 2019;11(8):e9266. doi:10.15252/emmm.201809266
34. Cancilla D, Rettig MP, DiPersio JF. Targeting CXCR4 in AML and ALL. Front Oncol. 2020;10:1672. doi:10.3389/fonc.2020.01672
35. Spoo AC, Lübbert M, Wierda WG, Burger JA. CXCR4 is a prognostic marker in acute myelogenous leukemia. Blood. 2007;109:786-791. doi: 10.1182/blood-2006-05-024844
36. Burger JA, Bürkle A. The CXCR4 chemokine receptor in acute and chronic leukaemia: a marrow homing receptor and potential therapeutic target. Br J Haematol. 2007;137:288-296. doi:10.1111/j.1365-2141.2007. 06590.x
37. Konoplev S, Lin P, Yin CC, et al. CXC chemokine receptor 4 expression, CXC chemokine receptor 4 activation, and wild-type nucleophosmin are independently associated with unfavorable prognosis in patients with acute myeloid leukemia. Clin Lymphoma Myeloma Leuk. 2013;13: 686-692. doi:10.1016/j.clml.2013.05.013
38. Mannelli F, Cutini I, Gianfaldoni G, et al. CXCR4 expression accounts for clinical phenotype and outcome in acute myeloid leukemia. Cytometry B Clin Cytom. 2014;86(5):340-349. doi:10.1002/cytob.21156
39. Cao T, Jiang N, Liao H, Shuai X, Su J, Zheng Q. The FLT3-ITD mutation and the expression of its downstream signaling intermediates STAT5 and Pim-1 are positively correlated with CXCR4 expression in patients with acute myeloid leukemia. Sci Rep. 2019;9(1):12209. doi:10.1038/s41598-019-48687-z
40. Cao T, Ye Y, Liao H, et al. Relationship between CXC chemokine receptor 4 expression and prognostic significance in acute myeloid leukemia. Medicine. 2019;98(23):e15948. doi:10.1097/MD.0000000000015948
41. Du W, Lu C, Zhu X, et al. Prognostic significance of CXCR4 expression in acute myeloid leukemia. Cancer Med. 2019;8(15):6595-6603. doi:10. 1002/cam4.2535
42. Mohle R, Schittenhelm M, Failenschmid C, et al. Functional response of leukaemic blasts to stromal cell-derived factor-1 correlates with preferential expression of the chemokine receptor CXCR4 in acute myelomonocytic and lymphoblastic leukaemia. Br J Haematol. 2000; 110(3):563-572. doi:10.1046/j.1365-2141.2000.02157.x
43. Abraham M, Pereg Y, Bulvik B, et al. Single dose of the CXCR4 antagonist BL-8040 induces rapid mobilization for the collection of human CD34(+) cells in healthy volunteers. Clin Cancer Res. 2017; 23(22):6790-6801. doi:10.1158/1078-0432.CCR-16-2919
44. Carter JL, Hege K, Kalpage HA, et al. Targeting mitochondrial respiration for the treatment of acute myeloid leukemia. Biochem Pharmacol. 2020;182:114253. doi:10.1016/j.bcp.2020.114253
45. Kovacsovics TJ, Mims A, Salama ME, et al. Combination of the low anticoagulant heparin CX-01 with chemotherapy for the treatment of acute myeloid leukemia. Blood Adv. 2018;2(4):381-389. doi:10.1182/bloodadvances.2017013391
46. Kulsoom B, Shamsi TS, Afsar NA, Memon Z, Ahmed N, Hasnain SN. Bax, Bcl-2, and Bax/Bcl-2 as prognostic markers in acute myeloid leukemia: are we ready for Bcl-2-directed therapy? Cancer Manag Res. 2018;10:403-416. doi:10.2147/CMAR.S154608
47. Pelcovits A, Niroula R. Acute myeloid leukemia: a review. R I Med J (2013). 2020;103(3):38-40.
48. Bode AM, Dong Z. Post-translational modification of p53 in tumorigenesis. Nat Rev Cancer. 2004;4(10):793-805. doi:10.1038/nrc1455
49. George B, Kantarjian H, Baran N, Krocker JD, Rios A. TP53 in Acute myeloid leukemia: molecular aspects and patterns of mutation. Int J Mol Sci. 2021;22(19):10782. doi:10.3390/ijms221910782
50. Vassilev LT, Vu BT, Graves B, et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science. 2004;303(5659):844-848. doi:10.1126/science.1092472
51. Droegemeier K. BCL2/MDM2 inhibitor combo effective in AML. Cancer Discov. 2019;9(2):156. doi:10.1158/2159-8290.CD-NB2019-003
52. Liu J, Liu M, Chen L. Novel pathogenesis: regulation of apoptosis by Apelin/APJ system.Acta Biochim Biophys Sin (Shanghai). 2017;49(6): 471-478. doi:10.1093/abbs/gmx035
53. Zhang Z, Yu B, Tao GZ. Apelin protects against cardiomyocyte apoptosis induced by glucose deprivation. Chin Med J. 2009;122(19):2360-2365. doi:10.3760/cma.j.issn.0366-6999.2009.19.031
54. Xin M, Deng X. Nicotine inactivation of the proapoptotic function of Bax through phosphorylation. J Biol Chem. 2005;280(11):10781-10789. doi:10.1074/jbc.M500084200
55. Burgering BM, Medema RH. Decisions on life and death: FOXO Forkhead transcription factors are in command when PKB/Akt is off duty. J Leukoc Biol. 2003;73(6):689-701. doi:10.1189/jlb.1202629
56. Mayo LD, Donner DB. The PTEN, Mdm2, p53 tumor suppressoroncoprotein network. Trends Biochem Sci. 2002;27(9):462-467. doi:10.1016/s0968-0004(02)02166-7
57. Hassan AS, Hou J, Wei W, Hoodless PA. Expression of two novel transcripts in the mouse definitive endoderm. Gene Expr Patterns. 2010;10(2-3):127-134. doi:10.1016/j.gep.2010.02.001
58. Choe W, Albright A, Sulcove J, et al. Functional expression of the seven-transmembrane HIV-1 co-receptor APJ in neural cells. J Neurovirol. 2000;6(Suppl 1):S61-69.
59. Seo JY, Kim DY, Kim SH, et al. Heterogeneous nuclear ribonucleoprotein (hnRNP) L promotes DNA damage-induced cell apoptosis by enhancing the translation of p53. Oncotarget. 2017;8(31):51108-51122. doi:10.18632/oncotarget.17003
60. Oliner JD, Saiki AY, Caenepeel S. The role of MDM2 ampli?cation and overexpression in tumorigenesis. Cold Spring Harb Perspect Med. 2016; 6(6):a026336. doi:10.1101/cshperspect.a026336
61. Kawauchi K, Ogasawara T, Yasuyama M, Otsuka K, Yamada O. The PI3K/Akt pathway as a target in the treatment of hematologic malignancies. Anticancer Agents Med Chem. 2009;9(5):550-559. doi:10. 2174/187152009788451851
62. Ma XM, Blenis J. Molecular mechanisms of mTOR-mediated translational control. Nat Rev Mol Cell Biol. 2009;10(5):307-318. doi:10. 1038/nrm2672
63. Ramanathan A, Schreiber SL. Direct control of mitochondrial function by mTOR. Proc Natl Acad Sci USA. 2009;106(52):22229-22232. doi:10. 1073/pnas.0912074106
64. Cunningham JT, Rodgers JT, Arlow DH, Vazquez F, Mootha VK, Puigserver P. mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex. Nature. 2007;450(7170):736-740. doi:10.1038/nature06322
65. Rabinowitz JD, White E. Autophagy and metabolism. Science. 2010; 330(6009):1344-1348. doi:10.1126/science.1193497
66. Hoshii T, Tadokoro Y, Naka K, et al. mTORC1 is essential for leukemia propagation but not stem cell self-renewal. J Clin Invest. 2012;122(6): 2114-2129. doi:10.1172/JCI62279
67. Porta C, Paglino C, Mosca A. Targeting PI3K/Akt/mTOR signaling in cancer. Front Oncol. 2014;4:64. doi:10.3389/fonc.2014.00064
68. Shakoori A, Ougolkov A, Yu ZW, et al. Deregulated GSK3beta activity in colorectal cancer: its association with tumor cell survival and proliferation. Biochem Biophys Res Commun. 2005;334(4):1365-1373. doi:10.1016/j.bbrc.2005.07.041
69. Park YL, Kim HP, Cho YW, et al. Activation of WNT/β-catenin signaling results in resistance to a dual PI3K/mTOR inhibitor in colorectal cancer cells harboring PIK3CA mutations. Int J Cancer. 2019; 144(2):389-401. doi:10.1002/ijc.31662
70. Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell. 2003;115(5):577-590. doi:10.1016/s0092-8674(03)00929-2
71. Gwinn DM, Shackelford DB, Egan DF, et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell. 2008;30(2):214-226. doi:10.1016/j.molcel.2008.03.003
72. Herzig S, Shaw RJ. AMPK: guardian of metabolism and mitochondrial homeostasis. Nat Rev Mol Cell Biol. 2018;19(2):121-135. doi:10.1038/nrm.2017.95
73. Luo H, Li Q, O’Neal J, Kreisel F, Le Beau MM, Tomasson MH. c-Myc rapidly induces acute myeloid leukemia in mice without evidence of lymphoma-associated antiapoptotic mutations. Blood. 2005;106(7): 2452-2461. doi:10.1182/blood-2005-02-0734
74. Biver E, Thouverey C, Magne D, Caverzasio J. Crosstalk between tyrosine kinase receptors, GSK3 and BMP2 signaling during osteoblastic differentiation of human mesenchymal stem cells. Mol Cell Endocrinol. 2014;382(1):120-130. doi:10.1016/j.mce.2013.09.018
75. Banerji V, Frumm SM, Ross KN, et al. The intersection of genetic and chemical genomic screens identifies GSK-3α as a target in human acute myeloid leukemia. J Clin Invest. 2012;122(3):935-947. doi:10.1172/JCI 46465
76. Rubinfeld B, Albert I, Porfiri E, Fiol C, Munemitsu S, Polakis P. Binding of GSK3beta to the APC-beta-catenin complex and regulation of complex assembly. Science. 1996;272(5264):1023-1026. doi:10.1126/science.272.5264.1023
77. Rayasam GV, Tulasi VK, Sodhi R, Davis JA, Ray A. Glycogen synthase kinase 3: more than a namesake. Br J Pharmacol. 2009;156(6):885-898. doi:10.1111/j.1476-5381.2008.00085.x
78. Soulet F, Bodineau C, Hooks KB, et al. ELA/APELA precursor cleaved by furin displays tumor suppressor function in renal cell carcinoma through mTORC1 activation. JCI Insight. 2020;5(14):e129070. doi:10. 1172/jci.insight.129070
79. Shen Y, Liu S, Fan J, et al. Nuclear retention of the lncRNA SNHG1 by doxorubicin attenuates hnRNPC-p53 protein interactions. EMBO Rep. 2017;18(4):536-548. doi:10.15252/embr.201643139
80. Wald O, Shapira OM, Izhar U. CXCR4/CXCL12 axis in non small cell lung cancer (NSCLC) pathologic roles and therapeutic potential. Theranostics. 2013;3(1):26-33. doi:10.7150/thno.4922
81. Franco R, Pirozzi G, Scala S, et al. CXCL12-binding receptors expression in non-small cell lung cancer relates to tumoral microvascular density and CXCR4 positive circulating tumoral cells in lung draining venous blood. Eur J Cardiothorac Surg. 2012;41(2):368-375. doi:10.1016/j.ejcts. 2011.05.009
82. Rodriguez-Lara V, Peña-Mirabal E, Baez-Saldaña R, et al. Estrogen receptor beta and CXCR4/CXCL12 expression: differences by sex and hor monal status in lung adenocarcinoma. Arch Med Res. 2014;45(2): 158-169. doi:10.1016/j.arcmed.2014.01.001
83. Wang M, Lin T, Wang Y, et al. CXCL12 suppresses cisplatin-induced apoptosis through activation of JAK2/STAT3 signaling in human non-small-cell lung cancer cells. Onco Targets Ther. 2017;10:3215-3224. doi: 10.2147/OTT.S133055
84. Pei S, Minhajuddin M, Adane B, et al. AMPK/FIS1-mediated mitophagy is required for self-renewal of human AML stem cells. Cell Stem Cell. 2018;23(1):86-100.e6. doi:10.1016/j.stem.2018.05.021
85. Bosc C, Broin N, Fanjul M, et al. Autophagy regulates fatty acid availability for oxidative phosphorylation through mitochondria-endoplasmic reticulum contact sites. Nat Commun. 2020;11(1):4056. doi:10.1038/s41467-020-17882-2
86. Levy JMM, Towers CG, Thorburn A. Targeting autophagy in cancer. Nat Rev Cancer. 2017;17(9):528-542. doi:10.1038/nrc.2017.53
87. Amaravadi R, Kimmelman AC, White E. Recent insights into the function of autophagy in cancer. Genes Dev. 2016;30:1913-1930. doi:10. 1101/gad.287524.116
88. White E. Deconvoluting the context-dependent role for autophagy in cancer. Nat Rev Cancer. 2012;12:401-410. doi:10.1038/nrc3262
89. Rabanal-Ruiz Y, Otten EG, Korolchuk VI. mTORC1 as the main gateway to autophagy. Essays Biochem. 2017;61(6):565-584. doi:10.1042/EBC20170027
90. Altman JK, Sassano A, Kaur S, et al. Dual mTORC2/mTORC1 targeting results in potent suppressive effects on acute myeloid leukemia (AML) progenitors. Clin Cancer Res. 2011;17(13):4378-4388. doi:10.1158/1078-0432.CCR-10-2285
91. Mancinelli R, Carpino G, Petrungaro S, et al. Multifaceted roles of GSK-3 in cancer and autophagy-related diseases. Oxid Med Cell Longev. 2017;2017:4629495. doi:10.1155/2017/4629495
92. Mendel DBLA, Xin X, Louie SG, et al. In vivo anti-tumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res. 2003;9(1):327-337.
93. Wu M, Li C, Zhu X. FLT3 inhibitors in acute myeloid leukemia. J Hematol Oncol. 2018;11(1):133. doi:10.1186/s13045-018-0675-4
Volume 3, Issue 3, 2025
Page : 67-73
_Footer