Upregulated hypoxia inducible factor 1α signaling pathway in high risk myelodysplastic syndrome and acute myeloid leukemia patients is associated with better response to 5-azacytidine-data from the Hellenic myelodysplastic syndrome study group.
5-azacytidine (5-ΑΖΑ)
hypoxia inducible factor 1 alpha (Hif-1α) signaling pathway
immunohistochemistry (IHC)
myelodysplastic syndrome (MDS)
quantitative real-time PCR
treatment response
Journal
Hematological oncology
ISSN: 1099-1069
Titre abrégé: Hematol Oncol
Pays: England
ID NLM: 8307268
Informations de publication
Date de publication:
Apr 2021
Apr 2021
Historique:
revised:
09
10
2020
received:
30
06
2020
accepted:
15
12
2020
pubmed:
18
12
2020
medline:
22
4
2021
entrez:
17
12
2020
Statut:
ppublish
Résumé
5-azacytidine (5-AZA) is considered the standard of care for patients with high-risk myelodysplastic syndromes (MDS) and patients with acute myeloid leukemia (AML) not candidate for intensive chemotherapy. However, even after an initial favorable response, almost all patients relapse, with the exact mechanisms underlying primary or secondary 5-AZA resistance remaining largely unknown. Several reports have previously demonstrated the significance of hypoxia in the regulation of both physiological and malignant hematopoiesis. In MDS, high hypoxia inducible factor 1α (Hif-1α) expression has been correlated with poor overall survival and disease progression, while its involvement in the disease's pathogenesis was recently reported. We herein investigated the possible association of the Hif-1α signaling pathway with response to 5-AZA therapy in MDS/AML patients. Our data demonstrated that 5-AZA-responders present with higher Hif-1α mRNA and protein expression compared to 5-AZA-non-responders/stable disease patients, before the initiation of therapy, while, interestingly, no significant differences in Hif-1α mRNA expression at the 6-month follow-up were observed. Moreover, we found that 5-AZA-responders exhibited elevated mRNA levels of the Hif-1α downstream targets lactate dehydrogenase a (LDHa) and BCL2 interacting protein 3 like (BNIP3L), a further indication of an overactivated Hif-1a signaling pathway in these patients. Kaplan-Meier survival analysis revealed a significant correlation between high Hif-1α mRNA expression and better survival rates, while logistic regression analysis showed that Hif-1α mRNA expression is an independent predictor of response to 5-AZA therapy. From the clinical point of view, apart from proposing Hif-1α mRNA expression as a significant predictive factor for response to 5-AZA, our data offer new perspectives on MDS combinational therapies, suggesting a potential synergistic activity of 5-AZA and Hif-1α inducers, such as propyl hydroxylases inhibitors (PHDi).
Substances chimiques
Antimetabolites, Antineoplastic
0
Hypoxia-Inducible Factor 1
0
Azacitidine
M801H13NRU
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
231-242Subventions
Organisme : Celgene
ID : GRANT-GRC-084
Informations de copyright
© 2020 John Wiley & Sons Ltd.
Références
Fenaux P , Mufti GJ , Hellstrom-Lindberg E , et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009;10(3):223-232.
Valencia A , Masala E , Rossi A , et al. Expression of nucleoside-metabolizing enzymes in myelodysplastic syndromes and modulation of response to azacitidine. Leukemia. 2014;28(3):621-628.
Montalban-Bravo G , Garcia-Manero G . Myelodysplastic syndromes: 2018 update on diagnosis, risk-stratification and management. Am J Hematol. 2018;93(1):129-147.
Lyons RM , Cosgriff TM , Modi SS , et al. Hematologic response to three alternative dosing schedules of azacitidine in patients with myelodysplastic syndromes. J Clin Oncol. 2009;27(11):1850-1856.
Garcia-Manero G , Gore SD , Cogle C , et al. Phase I study of oral azacitidine in myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia. J Clin Oncol. 2011;29(18):2521-2527.
Garcia-Manero G , Gore SD , Kambhampati S , et al. Efficacy and safety of extended dosing schedules of CC-486 (oral azacitidine) in patients with lower-risk myelodysplastic syndromes. Leukemia. 2016;30(4):889-896.
Irigoyen M , Garcia-Ruiz JC , Berra E . The hypoxia signalling pathway in haematological malignancies. Oncotarget. 2017;8(22):36832-36844.
Schito L , Rey S , Konopleva M . Integration of hypoxic HIF-alpha signaling in blood cancers. Oncogene. 2017;36(38):5331-5340.
Takubo K , Goda N , Yamada W , et al. Regulation of the HIF-1alpha level is essential for hematopoietic stem cells. Cell Stem Cell. 2010;7(3):391-402.
Semenza GL . HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. J Clin Invest. 2013;123(9):3664-3671.
Palazon A , Goldrath AW , Nizet V , Johnson RS . HIF transcription factors, inflammation, and immunity. Immunity. 2014;41(4):518-528.
Eltzschig HK , Abdulla P , Hoffman E , et al. HIF-1-dependent repression of equilibrative nucleoside transporter (ENT) in hypoxia. J Exp Med. 2005;202(11):1493-1505.
Wellmann S , Guschmann M , Griethe W , et al. Activation of the HIF pathway in childhood ALL, prognostic implications of VEGF. Leukemia. 2004;18(5):926-933.
Deeb G , Vaughan MM , McInnis I , et al. Hypoxia-inducible factor-1alpha protein expression is associated with poor survival in normal karyotype adult acute myeloid leukemia. Leuk Res. 2011;35(5):579-584.
Frolova O , Samudio I , Benito JM , et al. Regulation of HIF-1alpha signaling and chemoresistance in acute lymphocytic leukemia under hypoxic conditions of the bone marrow microenvironment. Canc Biol Ther. 2012;13(10):858-870.
Tong H , Hu C , Zhuang Z , Wang L , Jin J . Hypoxia-inducible factor-1alpha expression indicates poor prognosis in myelodysplastic syndromes. Leuk Lymphoma. 2012;53(12):2412-2418.
Coltella N , Percio S , Valsecchi R , et al. HIF factors cooperate with PML-RARalpha to promote acute promyelocytic leukemia progression and relapse. EMBO Mol Med. 2014;6(5):640-650.
Chen H , Shen Y , Gong F , Jiang Y , Zhang R . HIF-alpha promotes chronic myelogenous leukemia cell proliferation by upregulating p21 expression. Cell Biochem Biophys. 2015;72(1):179-183.
Du L , He R , Jiang Y , et al. mRNA Expression level and clinical value of hypoxia inducible factor 1 alpha in patients with myelodysplastic syndromes : a fluorescence quantitative real-time RT-PCR study. Int J Clin Exp Pathol. 2017;10(5):4979-4987.
Hayashi Y , Zhang Y , Yokota A , et al. Pathobiological pseudohypoxia as a putative mechanism underlying myelodysplastic syndromes. Canc Discov. 2018;8(11):1438-1457.
Pappa V , Anagnostopoulos A , Bouronikou E , et al. A retrospective study of azacitidine treatment in patients with intermediate-2 or high risk myelodysplastic syndromes in a real-world clinical setting in Greece. Int J Hematol. 2017;105(2):184-195.
Cheson BD , Greenberg PL , Bennett JM , et al. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006;108(2):419-425.
Semenza GL . Hypoxia-inducible factors in physiology and medicine. Cell. 2012;148(3):399-408.
Slemc L , Kunej T . Transcription factor HIF1A: downstream targets, associated pathways, polymorphic hypoxia response element (HRE) sites, and initiative for standardization of reporting in scientific literature. Tumour Biol. 2016;37(11):14851-14861.
Semenza GL , Jiang BH , Leung SW , et al. Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1. J Biol Chem. 1996;271(51):32529-32537.
Zhang H , Bosch-Marce M , Shimoda LA , et al. Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J Biol Chem. 2008;283(16):10892-10903.
Bellot G , Garcia-Medina R , Gounon P , et al. Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains. Mol Cell Biol. 2009;29(10):2570-2581.
White E , Mehnert JM , Chan CS . Autophagy, metabolism, and cancer. Clin Canc Res. 2015;21(22):5037-5046.
Lai MC , Chang CM , Sun HS . Hypoxia induces autophagy through translational up-regulation of lysosomal proteins in human colon cancer cells. PLoS One. 2016;11(4):e0153627.
Selak MA , Armour SM , MacKenzie ED , et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Canc Cell. 2005;7(1):77-85.
Frezza C , Pollard PJ , Gottlieb E . Inborn and acquired metabolic defects in cancer. J Mol Med Berl. 2011;89(3):213-220.
McCarty G , Loeb DM . Hypoxia-sensitive epigenetic regulation of an antisense-oriented lncRNA controls WT1 expression in myeloid leukemia cells. PLoS One. 2015;10(3):e0119837.
Velasco-Hernandez T , Hyrenius-Wittsten A , Rehn M , Bryder D , Cammenga J . HIF-1alpha can act as a tumor suppressor gene in murine acute myeloid leukemia. Blood. 2014;124(24):3597-3607.
Vukovic M , Guitart AV , Sepulveda C , et al. Hif-1alpha and Hif-2alpha synergize to suppress AML development but are dispensable for disease maintenance. J Exp Med. 2015;212(13):2223-2234.