Advances in New Targets for Differentiation Therapy of Acute Myeloid Leukemia
DOI:
https://doi.org/10.30683/1929-2279.2020.09.10Keywords:
Acute myeloid leukemia, differentiation therapy, cell cyclin-dependent kinase, homeobox genes.Abstract
Acute myeloid leukemia (AML) is a clinical and genetic heterogeneous disease with a poor prognosis. Recent advances in genomics and molecular biology have immensely improved the understanding of disease. The advantages of syndrome differentiation and treatment are strong selectivity, good curative effect and lesser side effects. In recent years, according to the molecular mechanism of acute myeloid leukemia, many new therapeutic targets have been found. New targets of differentiation therapy in recent years, such as cell cyclin-dependent kinase (CDK2), isocitrate dehydrogenase (IDH1, IDH2), Homeobox genes (HoxA9), Dihy-droorotate dehydrogenase (DHODH) and some others, are reviewed in this article.
References
Justin W, Stephen N. Recent advances in the understanding and treatment of acute myeloid leukemia[J]. F1000research 2018; 7: 1196-1210. https://doi.org/10.12688/f1000research.14116.1 DOI: https://doi.org/10.12688/f1000research.14116.1
Tenen DG. Disruption of differentiation in human cancer: AML shows the way[J]. Nat Rev Cancer 2003; 3: 89-101. https://doi.org/10.1038/nrc989 DOI: https://doi.org/10.1038/nrc989
Lowenberg B, Downing JR, Burnett A. Medical progress-acute myeloid leukemia[J]. New Engl J Med 1999; 341: 1051-1062. https://doi.org/10.1056/NEJM199909303411407 DOI: https://doi.org/10.1056/NEJM199909303411407
Angela, Walasek. The new perspectives of targeted therapy in acute myeloid leukemia[J]. Advances in Clinical & Experimental Medicine 2019; 28(2): 271-276. https://doi.org/10.17219/acem/81610 DOI: https://doi.org/10.17219/acem/81610
Chen Y, Pan Y, Guo Y, et al. Tyrosine kinase inhibitors targeting FLT3 in the treatmentof acute myeloid leukemia[J]. Stem Cell Investigation 2017; 4(6): 48. https://doi.org/10.21037/sci.2017.05.04 DOI: https://doi.org/10.21037/sci.2017.05.04
Kayser S, Levis MJ. Advances in targeted therapy for acute myeloid leukaemia[J]. British Journal of Haematology 2018; 180: 484-500. https://doi.org/10.1111/bjh.15032 DOI: https://doi.org/10.1111/bjh.15032
Madan V, Koeffler HP. Differentiation therapy of myeloid leukemia: four decades of development[J]. Blood 2021; 106(1): 26-38. https://doi.org/10.3324/haematol.2020.262121 DOI: https://doi.org/10.3324/haematol.2020.262121
Nowak D, Stewart D, Koeffler HP. Differentiation therapy of leukemia: 3 decades of development[J]. Blood 2009; 113(16): 3655-3665. https://doi.org/10.1182/blood-2009-01-198911 DOI: https://doi.org/10.1182/blood-2009-01-198911
Petrie K, Zelent A, Waxman S. Differentiation therapy of acute myeloid leukemia: past,present and future[J]. Curr Opin Hematol 2009; 16(2): 84-91. https://doi.org/10.1097/MOH.0b013e3283257aee DOI: https://doi.org/10.1097/MOH.0b013e3283257aee
Ying MD, Shao XJ, Jing H, et al. Ubiquitin-dependent degradation of CDK2 drives the therapeutic differentiation of AML by targeting PRDX2[J]. Blood 2018; 131(24): 2698-2711. https://doi.org/10.1182/blood-2017-10-813139 DOI: https://doi.org/10.1182/blood-2017-10-813139
Zhang J, Li H, Zhou T, et al. Cdk5 levels oscillate during the neuronal cell cycle: Cdh1 ubiquitination triggers proteosome dependent degradation during S-phase[J]. J Biol Chem 2012; 287(31): 25985-25994. https://doi.org/10.1074/jbc.M112.343152 DOI: https://doi.org/10.1074/jbc.M112.343152
Wang L, Zhou GB, Liu P, et al. Dissection of mechanisms of Chinese medicinal formula Realgar-Indigo naturalis as an effective treatment for promyelocytic leukemia[J]. Proc Natl Acad Sci USA 2008; 105(12): 4826-4831. https://doi.org/10.1073/pnas.0712365105 DOI: https://doi.org/10.1073/pnas.0712365105
Tikoo R, Casaccia-Bonnefil P, Chao MV, Koff A. Changes in cyclin-dependent kinase2 and p27kip1 accompany glial cell differentiation of central glia-4 cells[J]. J Biol Chem 1997; 272(1): 442-447. https://doi.org/10.1074/jbc.272.1.442 DOI: https://doi.org/10.1074/jbc.272.1.442
Fields S, Song O. A novel genetic system to detect protein-protein interactions[J]. Nature 1989; 340(6230): 245-246. https://doi.org/10.1038/340245a0 DOI: https://doi.org/10.1038/340245a0
Liu Z, Chen P, Gao H, et al. Ubiquitylation of autophagy receptor Optineurin by HACE1 activates selective autophagy for tumor suppression[J]. Cancer Cell 2014; 26(1): 106-120. https://doi.org/10.1016/j.ccr.2014.05.015 DOI: https://doi.org/10.1016/j.ccr.2014.05.015
Yang H, Ye D, Guan KL, et al. IDH1 and IDH2 mutations in tumorigenesis: mechanistic insights and clinical perspectives[J]. Clin Cancer Res 2012; 18(20): 5562-5571. https://doi.org/10.1158/1078-0432.CCR-12-1773 DOI: https://doi.org/10.1158/1078-0432.CCR-12-1773
Reitman ZJ, Yan H. Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterationsat a crossroads of cellular metabolism[J]. J Natl Cancer Inst 2010; 102(13): 932-941. https://doi.org/10.1093/jnci/djq187 DOI: https://doi.org/10.1093/jnci/djq187
Fujii T, Khawaja MR, DiNardo CD, Atkins JT, Janku F. Targeting isocitrate dehydrogenase (IDH) in cancer[J]. Discov Med 2016; 21(117): 373-380.
Lu C, Ward PS, Kapoor GS, et al. Abdel-Wahab O,et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation[J]. Nature 2012; 483(7390): 474-478. https://doi.org/10.1038/nature10860 DOI: https://doi.org/10.1038/nature10860
Yen KE, Bittinger MA, Su SM, et al. Cancer-associated IDH mutations: biomarker andtherapeutic opportunities[J]. Oncogene 2010; 29(49): 6409-6417. https://doi.org/10.1038/onc.2010.444 DOI: https://doi.org/10.1038/onc.2010.444
Dang L, Jin S, Su SM. IDH mutations in glioma and acute myeloid leukemia[J]. Trends Mol Med 2010; 16(9): 387-397. https://doi.org/10.1016/j.molmed.2010.07.002 DOI: https://doi.org/10.1016/j.molmed.2010.07.002
Dang L, White DW, Gross S, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate[J]. Nature 2009; 462(7274): 739. https://doi.org/10.1038/nature08617 DOI: https://doi.org/10.1038/nature08617
Xu W, Yang H, Liu Y, et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases[J]. Cancer Cell 2011; 19(1): 17-30. https://doi.org/10.1016/j.ccr.2010.12.014 DOI: https://doi.org/10.1016/j.ccr.2010.12.014
Figueroa ME, Wahab OA, Lu C, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation[J]. Cancer Cell 2010; 18(6): 553-567. https://doi.org/10.1016/j.ccr.2010.11.015 DOI: https://doi.org/10.1016/j.ccr.2010.11.015
Ward PS, Cross JR, Lu C, et al. Identification of additional IDH mutations associatedwith on cometabolite R(-)-2-hydroxyglutarate production[J]. Oncogene 2012; 31(19): 2491-2498. https://doi.org/10.1038/onc.2011.416 DOI: https://doi.org/10.1038/onc.2011.416
Abbas S, Lugthart S, Kavelaars FG, et al. Acquired mutations in the genes encoding IDH1 and IDH2 both are recurrent aberrations in acute myeloid leukemia: prevalence and prognostic value[J]. Blood 2010; 116(12): 2122-2126. https://doi.org/10.1182/blood-2009-11-250878 DOI: https://doi.org/10.1182/blood-2009-11-250878
Marcucci G, Maharry K, Wu YZ, et al. IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a Cancer And Leukemia Group B Study[J]. J Clin Oncol 2010; 28(14): 2348-2355. https://doi.org/10.1200/JCO.2009.27.3730 DOI: https://doi.org/10.1200/JCO.2009.27.3730
Paschka P, Schlenk RF, Gaidzik VI, et al. IDH1 and IDH2 mutations are frequent genetic alterations in acute myeloid leukemia and confer adverse prognosis in cytogenetically normal acute myeloid leukemia with NPM1 mutation without FLT3 internal tandem duplication[J]. J Clin Oncol 2010; 28(22): 3636-3643. https://doi.org/10.1200/JCO.2010.28.3762 DOI: https://doi.org/10.1200/JCO.2010.28.3762
DiNardo CD, Ravandi F, Agresta S, et al. Characteristics, clinical outcome, and prognostic significance of IDH mutations in AML[J]. Am J Hematol 2015; 90(8): 732-73. https://doi.org/10.1002/ajh.24072 DOI: https://doi.org/10.1002/ajh.24072
Chou WC, Lei WC, Ko BS, et al. The prognostic impact and stability of isocitrate dehydrogenase 2 mutation in adult patients with acute myeloid leukemia[J]. Leukemia 2011; 25(2): 246-253. https://doi.org/10.1038/leu.2010.267 DOI: https://doi.org/10.1038/leu.2010.267
Medeiros BC, Fathi A T, DiNardo CD, et al. Isocitrate dehydrogenase mutations in myeloid malignancies[J]. Leukemia 2017; 31(2): 272-281. https://doi.org/10.1038/leu.2016.275 DOI: https://doi.org/10.1038/leu.2016.275
Stein EM. IDH2 inhibition in AML: finally progress?[J] Best Pract Res Clin Haematol 2015; 28(2-3): 112-115. https://doi.org/10.1016/j.beha.2015.10.016 DOI: https://doi.org/10.1016/j.beha.2015.10.016
Platt MY, Fathi AT, Borger DR, et al. Detection of dual IDH1 and IDH2 mutations by targeted next-generation sequencing in acute myeloid leukemia and myelodysplastic syndromes[J]. J Molr Diagnostics 2015; 17(6): 661-668. https://doi.org/10.1016/j.jmoldx.2015.06.004 DOI: https://doi.org/10.1016/j.jmoldx.2015.06.004
Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic classification and prognosisin acute myeloid leukemia[J]. N Engl J Med 2016; 374(23): 2209-2221. https://doi.org/10.1056/NEJMoa1516192 DOI: https://doi.org/10.1056/NEJMoa1516192
Wang F, Travins J, DeLaBarre B, et al. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation[J]. Science 2013; 340(6132): 622-626. https://doi.org/10.1126/science.1234769 DOI: https://doi.org/10.1126/science.1234769
Braekeleer ED, Douet-Guilbert N, Basinko A, et al. Hox gene dysregulation in acute myeloid leukemia[J]. Future Oncol 2014; 10: 475‐495. https://doi.org/10.2217/fon.13.195 DOI: https://doi.org/10.2217/fon.13.195
Taniguchi Y. Hox transcription factors: modulators of cell‐cell and cellextracellular matrix adhesion[J]. Biomed Res Int 2014; 2014: 1-12. https://doi.org/10.1155/2014/591374 DOI: https://doi.org/10.1155/2014/591374
Andreeff M, Ruvolo V, Gadgil S, et al. HOX expression patterns identify a common signature for favorable AML[J]. Leukemia 2008; 22: 2041‐2047. https://doi.org/10.1038/leu.2008.198 DOI: https://doi.org/10.1038/leu.2008.198
Collins C, Wang J, Miao H, et al. C/EBPalpha is an essential collaborator in Hoxa9/Meis1‐mediated leukemogenesis[J]. Proc Natl Acad Sci USA 2014; 111: 9899‐9904. https://doi.org/10.1073/pnas.1402238111 DOI: https://doi.org/10.1073/pnas.1402238111
Tholouli E, MacDermott S, Hoyland J, et al. Quantitative multiplex quantum dot in-situ hybridisation basedgene expression profiling in tissue microarrays identifies prognostic genes in acute myeloid leukaemia[J]. Biochem Biophys Res Commun 2012; 425: 333‐339. https://doi.org/10.1016/j.bbrc.2012.07.092 DOI: https://doi.org/10.1016/j.bbrc.2012.07.092
Figueroa ME, Lugthart S, Li Y, et al. DNA methylation signatures identify biologically distinct subtypes in acute myeloidleukemia[J]. Cancer Cell 2010; 17: 13‐27. https://doi.org/10.1016/j.ccr.2009.11.020 DOI: https://doi.org/10.1016/j.ccr.2009.11.020
Karakas T, Maurer U, Weidmann E, et al. High expression of bcl-2 mRNA as a determinant of poor prognosis in acute myeloid leukemia[J]. Ann Oncol 1998; 9: 159-165. 43. https://doi.org/10.1023/A:1008255511404 DOI: https://doi.org/10.1023/A:1008255511404
Levine RL, Hoogenraad NJ, Kretchmer N. A review: biological and clinical aspects of pyrimidine metabolism[J]. Pediatr Res 1974; 8(7): 724-734. https://doi.org/10.1203/00006450-197407000-00008 DOI: https://doi.org/10.1203/00006450-197407000-00008
DeBerardinis RJ, Lum JJ, Hatzivassiliou G, et al. The biology of cancer:metabolic reprogramming fuels cell growth and proliferation[J]. Cell Metab 2008; 7: 11-20. https://doi.org/10.1016/j.cmet.2007.10.002 DOI: https://doi.org/10.1016/j.cmet.2007.10.002
Sykes DB, Kfoury YS, Mercier FE, et al. Inhibition of dihydroorotate dehydrogenaseovercomes differentiation blockade in acute myeloid leukemia[J]. Cell 2016; 167(1): 171-186. https://doi.org/10.1016/j.cell.2016.08.057 DOI: https://doi.org/10.1016/j.cell.2016.08.057
Zeng Z, Konopleva M. Targeting dihydroorotate dehydrogenase in acute myeloid leukemia[J]. Haematologica 2018; 103(9): 1415-1417. https://doi.org/10.3324/haematol.2018.197806 DOI: https://doi.org/10.3324/haematol.2018.197806
Carotta S, Wu L, Nutt SL. Surprising new roles for PU.1 in the adaptive immune response[J]. Immunol. Rev 2010; 238: 63-75. https://doi.org/10.1111/j.1600-065X.2010.00955.x DOI: https://doi.org/10.1111/j.1600-065X.2010.00955.x
Seshire A, Rößiger T., Frech M., et al. Direct interaction of PU.1 with oncogenic transcription factors reduces its serine phosphorylation and promoter binding[J]. Leukemia 2012; 26: 1338-1347. https://doi.org/10.1038/leu.2011.331 DOI: https://doi.org/10.1038/leu.2011.331
Gu X, Ebrahem Q, Mahfouz RZ, et al. Leukemogenic nucleophosmin mutation disrupts the transcription factor hub that regulates granulomonocyticfates[J]. J Clin Invest 2018; 128: 4260-4279. https://doi.org/10.1172/JCI97117 DOI: https://doi.org/10.1172/JCI97117
Ley TJ, Miller C, Ding L, et al. Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia[J]. N Engl J Med 2013; 368: 2059-2074. https://doi.org/10.1056/NEJMoa1301689 DOI: https://doi.org/10.1056/NEJMoa1301689
Cusan M, Cai SF, Mohammad HP, et al. LSD1 inhibition exerts its antileukemiceffect by recommissioning PU.1-and C/EBPa-dependent enhancers in AML[J]. Blood 2018; 131: 1730-1742. https://doi.org/10.1182/blood-2017-09-807024 DOI: https://doi.org/10.1182/blood-2017-09-807024
Mueller BU, Pabs T, Fos J, et al. ATRA resolves the differentiation block in t(15;17) acute myeloid leukemia by restoring PU.1 expression[J]. Blood 2006; 107: 3330-3338. https://doi.org/10.1182/blood-2005-07-3068 DOI: https://doi.org/10.1182/blood-2005-07-3068
Evrard M, Kwok IWH, Chong SZ, et al. Development alanalysis of bone marrow neutrophils reveals populations specialized in expansion, trafficking, and effector functions[J]. Immunity 2018; 48: 364-379. https://doi.org/10.1016/j.immuni.2018.02.002 DOI: https://doi.org/10.1016/j.immuni.2018.02.002
McKenzie MD, Margherita G, Ethan PO, et al. Interconversion between Tumorigenic and Differentiated States in Acute Myeloid Leukemia[J]. Cell Stem Cell 2019; 25(2): 258-272. https://doi.org/10.1016/j.stem.2019.07.001 DOI: https://doi.org/10.1016/j.stem.2019.07.001
Rosnet O, Stephenson D, Mattei MG, et al. Close physical linkage of the FLT1 and FLT3 genes on chromosome 13 in man and chromosome 5 in mouse[J]. Oncogene 1993; 8:173-179.
Agnes F, Shamoon B, Dina C, et al. Genomic structure of the downstream part of the human FL T3 gene: exon/intron structure conservation among genes encoding receptor tyrosine kinases (RTK) of subclass III[J]. Gene 1994; 145: 283-288. https://doi.org/10.1016/0378-1119(94)90021-3 DOI: https://doi.org/10.1016/0378-1119(94)90021-3
Lyman SD, James L, Zappone J, et al. Characterization of the protein encoded by the flt3 (flk2) receptor-like tyrosine kinase gene[J]. Oncogene 1993; 8: 815-822.
Carow CE, Levenstein M, Kaufmann SH, et al. Expression of the hematopoietic growth factor receptor FLT3 (STK-1/Flk2) in human leukemias[J]. Blood 1996; 87: 1089-1096. https://doi.org/10.1182/blood.V87.3.1089.bloodjournal8731089 DOI: https://doi.org/10.1182/blood.V87.3.1089.bloodjournal8731089
Rosnet O, Schiff C, Pebusque MJ, et al. Human FLT3/FLK2 gene: cDNA cloning and expression in hematopoietic cells[J]. Blood 1993; 82: 1110-1119. https://doi.org/10.1182/blood.V82.4.1110.bloodjournal8241110 DOI: https://doi.org/10.1182/blood.V82.4.1110.1110
Mackarehtschian K, Hardin JD, Moore KA, et al. Targeted disruption of the flk2/flt3 gene leads to deficiencies in primitive hematopoietic progenitors[J]. Immunity 1995; 3: 147-161. https://doi.org/10.1016/1074-7613(95)90167-1 DOI: https://doi.org/10.1016/1074-7613(95)90167-1
Gotze KS, Ramirez M, Tabor K, et al. Flt3high and Flt3low CD34+ progenitor cells isolated from human bone marrow are functionally distinct[J]. Blood 1998; 91: 1947-1958. https://doi.org/10.1182/blood.V91.6.1947.1947_1947_1958 DOI: https://doi.org/10.1182/blood.V91.6.1947.1947_1947_1958
Lyman SD. Biology of flt3 ligand and receptor[J]. Int J Hematol 1995; 62: 63-73. DOI: https://doi.org/10.1016/0925-5710(95)00389-A
Rosnet O, Bühring HJ, DeLapeyrière O, et al. Expression and signal transduction of the FLT3 tyrosine kinase receptor[J]. Acta Haematol 1996; 95: 218-223. https://doi.org/10.1159/000203881 DOI: https://doi.org/10.1159/000203881
Lavagna-Sevenier C, Marchetto S, Birnbaum D, et al. FLT3 signaling in hematopoietic cells involves CBL, SHC and an unknown P115 as prominent tyrosine-phosphorylated substrates[J]. Leukemia 1998; 12: 301-310. https://doi.org/10.1038/sj.leu.2400921 DOI: https://doi.org/10.1038/sj.leu.2400921
Cook AM, Li L, Ho Y, et al. Role of altered growth factor receptor-mediated JAK2 signaling in growth and maintenance of human acute myeloid leukemia stem cells[J]. Blood 2014; 123: 2826-2837. https://doi.org/10.1182/blood-2013-05-505735 DOI: https://doi.org/10.1182/blood-2013-05-505735
Zhang S, Broxmeyer HE. p85 subunit of PI3 kinase does not bind to human Flt3 receptor, but associates with SHP2, SHIP, and a tyrosine-phosphorylated 100-kDa protein In Flt3 ligand-stimulated hematopoietic cells[J]. Biochem Biophys Res Commun 1999; 254: 440-445. https://doi.org/10.1006/bbrc.1998.9959 DOI: https://doi.org/10.1006/bbrc.1998.9959
Zhang SL, Mantel C, Broxmeyer HE. Flt3 signaling involves tyrosyl-phosphorylation of SHP-2 and SHIP and their association with Grb2 and Shc in Baf3/Flt3 cells[J]. J Leukoc Biol 1999; 65: 372-380. https://doi.org/10.1002/jlb.65.3.372 DOI: https://doi.org/10.1002/jlb.65.3.372
Meierhoff G, Dehmel U, Gruss HJ, et al. Expression of FLT3 receptor and FLT3-ligand in human leukemia-lymphoma cell lines[J]. Leukemia 1995; 9: 1368-1372.
Hayakawa F, Towatari M, Kiyoi H, et al. Tandem-duplicated Flt3 constitutively activates STAT5 and MAP kinase and introduces autonomous cell growth in IL-3-dependent cell lines[J]. Oncogene 2000; 19: 624-631. https://doi.org/10.1038/sj.onc.1203354 DOI: https://doi.org/10.1038/sj.onc.1203354
Nakao M, Yokota S, Iwai T, et al. Internal tandem duplication of the flt3 gene found in acute myeloid leukemia[J]. Leukemia 1996; 10(12): 1911-1918.