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GADD45g acts as a novel tumor suppressor, and its activation suggests new combination regimens for the treatment of AML

Guo, Dan, Zhao, Yangyang, Wang, Nan, You, Na, Zhu, Wenqi, Zhang, Peiwen, Ren, Qian, Yin, Jing, Cheng, Tao, Ma, Xiaotong·2021·Blood
DOI 10.1182/blood.2020008229
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Abstract

Acute myeloid leukemia (AML) is an aggressive hematopoietic malignancy for which there is an unmet need for novel treatment strategies. Here, we characterize the growth arrest and DNA damage-inducible gene gamma (GADD45g) as a novel tumor suppressor in AML. We show that GADD45g is preferentially silenced in AML, especially in AML with FMS-like tyrosine kinase 3–internal tandem duplication (FLT3-ITD) mutations and mixed-lineage leukemia (MLL)-rearrangements, and reduced expression of GADD45g is correlated with poor prognosis in patients with AML. Upregulation of GADD45g impairs homologous recombination DNA repair, leading to DNA damage accumulation, and dramatically induces apoptosis, differentiation, and growth arrest and increases sensitivity of AML cells to chemotherapeutic drugs, without affecting normal cells. In addition, GADD45g is epigenetically silenced by histone deacetylation in AML, and its expression is further downregulated by oncogenes FLT3-ITD and MLL-AF9 in patients carrying these genetic abnormalities. Combination of the histone deacetylase 1/2 inhibitor romidepsin with the FLT3 tyrosine kinase inhibitor AC220 or the bromodomain inhibitor JQ1 exerts synergistic antileukemic effects on FLT3-ITD+ and MLL-AF9+ AML, respectively, by dually activating GADD45g. These findings uncover hitherto unreported evidence for the selective antileukemic role of GADD45g and provide novel strategies for the treatment of FLT3-ITD+ and MLL-AF9+ AML.

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Research works printed but not linked: 60

  1. Döhner, 2015, Acute myeloid leukemia, N Engl J Med., 373, 1136, 10.1056/NEJMra1406184 · DOI
  2. Estey, 2006, Acute myeloid leukaemia, Lancet., 368, 1894, 10.1016/S0140-6736(06)69780-8 · DOI
  3. Nazha, 2012, Activating internal tandem duplication mutations of the fms-like tyrosine kinase-3 (FLT3-ITD) at complete response and relapse in patients with acute myeloid leukemia, Haematologica., 97, 1242, 10.3324/haematol.2012.062638 · DOI
  4. Thiede, 2002, Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis, Blood., 99, 4326, 10.1182/blood.V99.12.4326 · DOI
  5. Krivtsov, 2007, MLL translocations, histone modifications and leukaemia stem-cell development, Nat Rev Cancer., 7, 823, 10.1038/nrc2253 · DOI
  6. Breems, 2005, Prognostic index for adult patients with acute myeloid leukemia in first relapse, J Clin Oncol., 23, 1969, 10.1200/JCO.2005.06.027 · DOI
  7. Sternberg, 2005, Therapeutic intervention in leukemias that express the activated fms-like tyrosine kinase 3 (FLT3): opportunities and challenges, Curr Opin Hematol., 12, 7, 10.1097/01.moh.0000147891.06584.d7 · DOI
  8. Nechiporuk, 2019, The TP53 apoptotic network is a primary mediator of resistance to BCL2 inhibition in AML cells, Cancer Discov., 9, 910, 10.1158/2159-8290.CD-19-0125 · DOI
  9. Bell, 2019, Targeting enhancer switching overcomes non-genetic drug resistance in acute myeloid leukaemia, Nat Commun., 10, 2723, 10.1038/s41467-019-10652-9 · DOI
  10. Short, 2018, Acute myeloid leukaemia, Lancet., 392, 593, 10.1016/S0140-6736(18)31041-9 · DOI
  11. Mandal, 2011, DNA damage response in adult stem cells: pathways and consequences, Nat Rev Mol Cell Biol., 12, 198, 10.1038/nrm3060 · DOI
  12. Tubbs, 2017, Endogenous DNA damage as a source of genomic instability in cancer, Cell., 168, 644, 10.1016/j.cell.2017.01.002 · DOI · Paper page
  13. Esposito, 2015, Synthetic lethal targeting of oncogenic transcription factors in acute leukemia by PARP inhibitors, Nat Med., 21, 1481, 10.1038/nm.3993 · DOI
  14. Brown, 2017, Targeting DNA repair in cancer: beyond PARP inhibitors, Cancer Discov., 7, 20, 10.1158/2159-8290.CD-16-0860 · DOI
  15. Liebermann, 2011, Gadd45 stress sensors in malignancy and leukemia, Crit Rev Oncog., 16, 129, 10.1615/CritRevOncog.v16.i1-2.120 · DOI
  16. Cretu, 2009, Stress sensor Gadd45 genes as therapeutic targets in cancer, Cancer Ther., 7, 268
  17. Vairapandi, 2002, GADD45b and GADD45g are cdc2/cyclinB1 kinase inhibitors with a role in S and G2/M cell cycle checkpoints induced by genotoxic stress, J Cell Physiol., 192, 327, 10.1002/jcp.10140 · DOI
  18. Perugini, 2013, GADD45A methylation predicts poor overall survival in acute myeloid leukemia and is associated with IDH1/2 and DNMT3A mutations, Leukemia., 27, 1588, 10.1038/leu.2012.346 · DOI
  19. Mukherjee, 2017, Gadd45a deficiency accelerates BCR-ABL driven chronic myelogenous leukemia, Oncotarget., 8, 10809, 10.18632/oncotarget.14580 · DOI
  20. Sha, 2018, Loss of Gadd45b accelerates BCR-ABL-driven CML, Oncotarget., 9, 33360, 10.18632/oncotarget.26076 · DOI
  21. Barretina, 2012, The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity [published correction appears in Nature. 2012;492(7428):290], Nature., 483, 603, 10.1038/nature11003 · DOI · Paper page
  22. Kohlmann, 2008, An international standardization programme towards the application of gene expression profiling in routine leukaemia diagnostics: the Microarray Innovations in LEukemia study prephase, Br J Haematol., 142, 802, 10.1111/j.1365-2141.2008.07261.x · DOI
  23. Martin, 2012, Genome-wide analysis of pre-mRNA 3' end processing reveals a decisive role of human cleavage factor I in the regulation of 3' UTR length, Cell Rep., 1, 753, 10.1016/j.celrep.2012.05.003 · DOI
  24. Tomasson, 2008, Somatic mutations and germline sequence variants in the expressed tyrosine kinase genes of patients with de novo acute myeloid leukemia, Blood., 111, 4797, 10.1182/blood-2007-09-113027 · DOI
  25. Wang, 2016, RNF126 promotes homologous recombination via regulation of E2F1-mediated BRCA1 expression, Oncogene., 35, 1363, 10.1038/onc.2015.198 · DOI
  26. Degregori, 2011, A new role for E2F1 in DNA repair: all for the greater good, Cell Cycle., 10, 1716, 10.4161/cc.10.11.15649 · DOI
  27. Pellicano, 2018, hsa-mir183/EGR1-mediated regulation of E2F1 is required for CML stem/progenitor cell survival, Blood., 131, 1532, 10.1182/blood-2017-05-783845 · DOI
  28. Warr, 2012, Gadd45γ and Map3k4 interactions regulate mouse testis determination via p38 MAPK-mediated control of Sry expression, Dev Cell., 23, 1020, 10.1016/j.devcel.2012.09.016 · DOI
  29. Salvador, 2013, Gadd45 in stress signaling, cell cycle control, and apoptosis, Adv Exp Med Biol., 793, 1, 10.1007/978-1-4614-8289-5_1 · DOI · Paper page
  30. Thalheimer, 2014, Cytokine-regulated GADD45G induces differentiation and lineage selection in hematopoietic stem cells, Stem Cell Reports., 3, 34, 10.1016/j.stemcr.2014.05.010 · DOI
  31. Gubern, 2016, The N-terminal phosphorylation of RB by p38 bypasses its inactivation by CDKs and prevents proliferation in cancer cells, Mol Cell., 64, 25, 10.1016/j.molcel.2016.08.015 · DOI
  32. Ivanova, 2009, Phosphorylation by p38 MAP kinase is required for E2F1 degradation and keratinocyte differentiation, Oncogene., 28, 52, 10.1038/onc.2008.354 · DOI
  33. Na, 2010, Hypermethylation of growth arrest DNA-damage-inducible gene 45 in non-small cell lung cancer and its relationship with clinicopathologic features, Mol Cells., 30, 89, 10.1007/s10059-010-0092-1 · DOI
  34. Campanero, 2008, The histone deacetylase inhibitor trichostatin A induces GADD45 gamma expression via Oct and NF-Y binding sites, Oncogene., 27, 1263, 10.1038/sj.onc.1210735 · DOI
  35. Zerbini, 2004, NF-kappa B-mediated repression of growth arrest- and DNA-damage-inducible proteins 45alpha and gamma is essential for cancer cell survival [published correction appears in Proc Natl Acad Sci U S A. 2004;101(42): 15271], Proc Natl Acad Sci U S A., 101, 13618, 10.1073/pnas.0402069101 · DOI · Paper page
  36. Scuto, 2013, SIRT1 activation enhances HDAC inhibition-mediated upregulation of GADD45G by repressing the binding of NF-κB/STAT3 complex to its promoter in malignant lymphoid cells, Cell Death Dis., 4, e635, 10.1038/cddis.2013.159 · DOI · Paper page
  37. Ceribelli, 2014, Blockade of oncogenic IκB kinase activity in diffuse large B-cell lymphoma by bromodomain and extraterminal domain protein inhibitors, Proc Natl Acad Sci U S A., 111, 11365, 10.1073/pnas.1411701111 · DOI
  38. Sun, 2015, Synergistic activity of BET protein antagonist-based combinations in mantle cell lymphoma cells sensitive or resistant to ibrutinib [published correction appears in Blood. 2016;128(13):1778], Blood., 126, 1565, 10.1182/blood-2015-04-639542 · DOI
  39. Xiao, 2016, Bromodomain and extra-terminal domain bromodomain inhibition prevents synovial inflammation via blocking IκB kinase-dependent NF-κB activation in rheumatoid fibroblast-like synoviocytes, Rheumatology (Oxford)., 55, 173, 10.1093/rheumatology/kev312 · DOI
  40. Ju, 2009, Gadd45b and Gadd45g are important for anti-tumor immune responses, Eur J Immunol., 39, 3010, 10.1002/eji.200839154 · DOI
  41. Maifrede, 2018, Tyrosine kinase inhibitor-induced defects in DNA repair sensitize FLT3(ITD)-positive leukemia cells to PARP1 inhibitors, Blood., 132, 67, 10.1182/blood-2018-02-834895 · DOI
  42. Jacoby, 2014, The DNA double-strand break response is abnormal in myeloblasts from patients with therapy-related acute myeloid leukemia, Leukemia., 28, 1242, 10.1038/leu.2013.368 · DOI
  43. Cavelier, 2009, Constitutive activation of the DNA damage signaling pathway in acute myeloid leukemia with complex karyotype: potential importance for checkpoint targeting therapy, Cancer Res., 69, 8652, 10.1158/0008-5472.CAN-09-0939 · DOI
  44. Xu, 2019, hCINAP regulates the DNA-damage response and mediates the resistance of acute myelocytic leukemia cells to therapy, Nat Commun., 10, 3812, 10.1038/s41467-019-11795-5 · DOI
  45. Santos, 2014, DNA-damage-induced differentiation of leukaemic cells as an anti-cancer barrier, Nature., 514, 107, 10.1038/nature13483 · DOI
  46. Lord, 2017, PARP inhibitors: synthetic lethality in the clinic, Science., 355, 1152, 10.1126/science.aam7344 · DOI
  47. Lee, 2014, PARP inhibitors for BRCA1/2 mutation-associated and BRCA-like malignancies, Ann Oncol., 25, 32, 10.1093/annonc/mdt384 · DOI
  48. Parvin, 2019, LMO2 confers synthetic lethality to PARP inhibition in DLBCL, Cancer Cell., 36, 237, 10.1016/j.ccell.2019.07.007 · DOI
  49. Sullivan-Reed, 2018, Simultaneous targeting of PARP1 and RAD52 triggers dual synthetic lethality in BRCA-deficient tumor cells, Cell Rep., 23, 3127, 10.1016/j.celrep.2018.05.034 · DOI
  50. Wang, 2015, PARP inhibitors: a treatment option for AML?, Nat Med., 21, 1393, 10.1038/nm.4007 · DOI
  51. Zhao, 2016, PARP-inhibitor-induced synthetic lethality for acute myeloid leukemia treatment, Exp Hematol., 44, 902, 10.1016/j.exphem.2016.07.007 · DOI
  52. Faraoni, 2019, Targeting ADP-ribosylation by PARP inhibitors in acute myeloid leukaemia and related disorders, Biochem Pharmacol., 167, 133, 10.1016/j.bcp.2019.04.019 · DOI
  53. Noordermeer, 2019, PARP inhibitor resistance: a tug-of-war in BRCA-mutated cells, Trends Cell Biol., 29, 820, 10.1016/j.tcb.2019.07.008 · DOI
  54. Francica, 2018, Mechanisms of PARP inhibitor resistance in cancer and insights into the DNA damage response, Genome Med., 10, 101, 10.1186/s13073-018-0612-8 · DOI
  55. Sun, 2017, Romidepsin induces G2/M phase arrest via Erk/cdc25C/cdc2/cyclinB pathway and apoptosis induction through JNK/c-Jun/caspase3 pathway in hepatocellular carcinoma cells, Biochem Pharmacol., 127, 90, 10.1016/j.bcp.2016.12.008 · DOI
  56. San José-Enériz, 2019, HDAC inhibitors in acute myeloid leukemia, Cancers (Basel)., 11, E1794, 10.3390/cancers11111794 · DOI
  57. Yan, 2019, Histone deacetylase inhibitor targets CD123/CD47-positive cells and reverse chemoresistance phenotype in acute myeloid leukemia, Leukemia., 33, 931, 10.1038/s41375-018-0279-6 · DOI
  58. Fiskus, 2014, Highly active combination of BRD4 antagonist and histone deacetylase inhibitor against human acute myelogenous leukemia cells, Mol Cancer Ther., 13, 1142, 10.1158/1535-7163.MCT-13-0770 · DOI
  59. Pietschmann, 2012, Breakdown of the FLT3-ITD/STAT5 axis and synergistic apoptosis induction by the histone deacetylase inhibitor panobinostat and FLT3-specific inhibitors, Mol Cancer Ther., 11, 2373, 10.1158/1535-7163.MCT-12-0129 · DOI
  60. Tharkar-Promod, 2018, HDAC1,2 inhibition and doxorubicin impair Mre11-dependent DNA repair and DISC to override BCR-ABL1-driven DSB repair in Philadelphia chromosome-positive B-cell precursor acute lymphoblastic leukemia, Leukemia., 32, 49, 10.1038/leu.2017.174 · DOI

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Metadata

Authors
Guo, D., Zhao, Y., Wang, N., You, N., Zhu, W., Zhang, P., Ren, Q., Yin, J., Cheng, T., & Ma, X.
Venue
Blood
Publisher
American Society of Hematology
Published
2021-05-04
Volume
138
Issue
6
Pages
464-479
ISSN
  • 0006-4971
  • 1528-0020
DOI
10.1182/blood.2020008229
Cited by
36
References
5
Language
en

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CoChat. (2026). Citation check: GADD45g acts as a novel tumor suppressor, and its activation suggests new combination regimens for the treatment of AML. https://app.cochat.ai/papers/10.1182/blood.2020008229
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Guo, D., Zhao, Y., Wang, N., You, N., Zhu, W., Zhang, P., Ren, Q., Yin, J., Cheng, T., & Ma, X. (2021). GADD45g acts as a novel tumor suppressor, and its activation suggests new combination regimens for the treatment of AML. Blood. https://doi.org/10.1182/blood.2020008229