Integrative Genomics Identifies the Molecular Basis of Resistance to Azacitidine Therapy in Myelodysplastic Syndromes

Unnikrishnan, Ashwin; Papaemmanuil, Elli; Beck, Dominik; Deshpande, Nandan P.; Verma, Arjun; Kumari, Ashu; Woll, Petter S.; Richards, Laura A.; Knezevic, Kathy; Chandrakanthan, Vashe; Thoms, Julie A.I.; Tursky, Melinda L.; Huang, Yizhou; Ali, Zara; Olivier, Jake; Galbraith, Sally; Kulasekararaj, Austin; Tobiasson, Magnus; Karimi, Mohsen; Pellagatti, Andrea; Wilson, Susan R.; Lindeman, Robert; Young, Boris; Ramakrishna, Raj; Arthur, Christopher; Stark, Richard S.; Crispin, Philip; Curnow, Jennifer; Warburton, Pauline; Roncolato, Fernando; Boultwood, Jacqueline; Lynch, Kevin; Jacobsen, Sten Eirik W.; Mufti, Ghulam J.; Hellström‐Lindberg, Eva; Wilkins, Marc R.; MacKenzie, Karen L.; Wong, Jason; Campbell, Peter J.; Pimanda, John E.

doi:10.1016/j.celrep.2017.06.067

Cited by 108 publications

(110 citation statements)

References 49 publications

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“…This mode of learned resistance, emerging from adaptive responses of the pyrimidine metabolism network to pro-drug perturbations, does not require mutation at the genetic level, perhaps explaining why several studies that have looked for correlations between MDS/AML genetics and decitabine/5-azacytidine resistance have generated inconclusive and even contradictory results 4,[50][51][52][53][54][55][56] . Given that resistance-causing metabolic reconfigurations appear emergent, pre-treatment pyrimidine metabolism expression levels may also not necessarily predict response 4,[50][51][52][53][54][55][56][57][58] . Consistent and predictable, however, were the automatic adaptive responses of pyrimidine metabolism to pro-drug exposures, enabling anticipation, outmaneuvering and even exploitation:…”

Section: Discussionmentioning

confidence: 99%

Resistance to decitabine and 5-azacytidine emerges from adaptive responses of the pyrimidine metabolism network

Tohmé

Tomlinson³

et al. 2020

Preprint

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Mechanisms-of-resistance to decitabine and 5-azacytidine, mainstay treatments for myeloid malignancies, require investigation and countermeasures. Both are nucleoside analog pro-drugs processed by pyrimidine metabolism into a nucleotide analog that depletes the key epigenetic regulator DNA methyltranseferase 1 (DNMT1). We report here that DNMT1 protein, although substantially depleted (~50%) in patients' bone marrows at response, rebounded at relapse, and explaining this, we found pyrimidine metabolism gene expression shifts averse to the processing of each pro-drug. The same metabolic shifts observed clinically were rapidly recapitulated in leukemia cells exposed to the pro-drugs in vitro. Pyrimidine metabolism is a network that senses and preserves nucleotide balances: Decitabine, a deoxycytidine analog, and 5-azacytidine, a cytidine analog, caused acute and distinct nucleotide imbalances, by off-target inhibition of thymidylate synthase and ribonucleotide reductase respectively. Resulting expression changes in key pyrimidine metabolism enzymes peaked 72-96 hours later. Continuous pro-drug exposure stabilized metabolic shifts generated acutely, preventing DNMT1-depletion and permitting exponential leukemia out-growth as soon as day 40. Although dampening to activity of the pro-drug initially applied, adaptive metabolic responses primed for activity of the other. Hence, in xenotransplant models of chemorefractory AML, alternating decitabine with 5-azacytidine, timed to exploit compensating metabolic shifts, and addition of an inhibitor of a catabolic enzyme induced by decitabine/5-azacytidine, extended DNMT1-depletion and time-to-distress by several months versus either prodrug alone. In sum, resistance to decitabine and 5-azacytidine emerges from adaptive responses of the pyrimidine metabolism network; these responses can be anticipated and thus exploited.

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Section: Discussionmentioning

confidence: 99%

Resistance to decitabine and 5-azacytidine emerges from adaptive responses of the pyrimidine metabolism network

Tohmé

Tomlinson³

et al. 2020

Preprint

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“…AZA is a DNA methyltransferase inhibitor that has been successfully used in epigenetic neoplastic therapy to reactivate epigenetically silenced tumour suppressor genes . Furthermore, AZA is the first‐line treatment for patients with high‐risk myelodysplastic syndrome and has been successful in prolonging survival and delayed AML evolution . These findings prompted us to examine whether methylation‐mediated epigenetic silencing SPINT2/HAI‐2 was involved in Myelodysplastic Syndrome and de novo AML pathophysiology.…”

Section: Discussionmentioning

confidence: 99%

“…21 Furthermore, AZA is the first-line treatment for patients with high-risk myelodysplastic syndrome and has been successful in prolonging survival and delayed AML evolution. 22 These findings prompted us to examine whether methylation-mediated epigenetic silencing SPINT2/HAI-2 was involved in Myelodysplastic Syndrome and de novo AML pathophysiology.…”

Section: Discussionmentioning

confidence: 99%

Up‐regulation of SPINT2/HAI‐2 by Azacytidine in bone marrow mesenchymal stromal cells affects leukemic stem cell survival and adhesion

Roversi

Cury

Lopes

et al. 2018

J Cellular Molecular Medi

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The role of tumour microenvironment in neoplasm initiation and malignant evolution has been increasingly recognized. However, the bone marrow mesenchymal stromal cell (BMMSC) contribution to disease progression remains poorly explored. We previously reported that the expression of serine protease inhibitor kunitz‐type2 (SPINT2/HAI‐2), an inhibitor of hepatocyte growth factor (HGF) activation, is significantly lower in BMMSC from myelodysplastic syndromes (MDS) patients compared to healthy donors (HD). Thus, to investigate whether this loss of expression was due to SPINT2/HAI‐2 methylation, BMMSC from MDS and de novo acute myeloid leukaemia (de novo AML) patients were treated with 5‐Azacitidine (Aza), a DNA methyltransferase inhibitor. In MDS‐ and de novo AML‐BMMSC, Aza treatment resulted in a pronounced SPINT2/HAI‐2 levels up‐regulation. Moreover, Aza treatment of HD‐BMMSC did not improve SPINT2/HAI‐2 levels. To understand the role of SPINT2/HAI‐2 down‐regulation in BMMSC physiology, SPINT2/HAI‐2 expression was inhibited by lentivirus. SPINT2 underexpression resulted in an increased production of HGF by HS‐5 stromal cells and improved survival of CD34+ de novo AML cells. We also observed an increased adhesion of de novo AML hematopoietic cells to SPINT2/HAI‐2 silenced cells. Interestingly, BMMSC isolated from MDS and de novo AML patients had increased expression of the integrins CD49b, CD49d, and CD49e. Thus, SPINT2/HAI‐2 may contribute to functional and morphological abnormalities of the microenvironment niche and to stem/progenitor cancer cell progression. Hence, down‐regulation in SPINT2/HAI‐2 gene expression, due to methylation in MDS‐BMMSC and de novo AML‐BMMSC, provides novel insights into the pathogenic role of the leukemic bone marrow microenvironment.

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“…In this study we summarized the results of 12 studies with whole exome/genome sequencing in MDS [10,11,[13][14][15][16][17][18][19][20][21][22].…”

Section: Discussionmentioning

confidence: 99%

Meta-analysis of studies with genome sequencing in myelodysplastic syndrome treated with hypomethylating agents

Tsvetkov¹,

Epifanovskaya²,

Rudnitskaya³

et al. 2018

CTT

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SummaryMyelodysplastic syndrome represents a heterogenous group of clonal diseases affecting the hematopoietic stem cells underlied by different somatic gene mutations and/or altered epigenetic regulation induced by the disturbed microenvironment, as well as changes in the immune surveillance system. In many patients, the MDS is preceded by a period of non-clonal or clonal cytopenias of a non-clear significance that are determined by age-associated somatic mutations and increased leukemia risks resulting into a higher cellular proliferation, inefficient clonal growth, suppression of normal hematopoiesis, and, finally, into altered differentiation, thus causing accumulation of blast forms and a risk of evolving into acute leukemia. Substantial data on prevalence and impact of mutations on the prognosis in myelodysplastic syndrome was accessed by multiple groups however the results of several published studies are controversial. Thus we have performed an unconventional meta-analysis by accessing resulting confidence intervals both by statistical means and by creating pulled database with available individual patient data. 12 studies with 1238 patients were analyzed. The observed prevalence of mutations was the subject to significant variability (95%CI: ASXL1 13.6-29.8%; DNMT3A 7.3-12.9%; EZH2 2.4-7.0%; U2AF1 3.7-13.8%; TET2 14.2-32.5%; RUNX1 3.9-13.7%; TP53 4.7-15.2%; SRSF2 7.1-28.1%; RAS 2.2-15,1%; SF3B1 4.4-12.2%; CBL 0.1-8.9%; None, 8.0-23.3%; р<0.0001). The analysis of response to hypomethylating agents revealed improved response in patients with TP53 (95% CI 49-55%, p=0.0003), TET2(95% CI 49-52%, p=0.0001) and SRSF2 (95% CI 48-54%, p=0.0005) mutations; however the survival was worse in TP53 mutated patients (95% CI 44-49%, p=0.002) and better in SF3B1 mutated disease (95% CI 47-54%, p=0.01). The magnitude of difference was less than previously reported. The study confirmed the previous reports on the impact of TP53, TET2 and SF3B1 mutations on prognosis. Further studies on the potential prognostic markers are required, especially in patients with absence of conventional mutations.

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Integrative Genomics Identifies the Molecular Basis of Resistance to Azacitidine Therapy in Myelodysplastic Syndromes

Cited by 108 publications

References 49 publications

Resistance to decitabine and 5-azacytidine emerges from adaptive responses of the pyrimidine metabolism network

Resistance to decitabine and 5-azacytidine emerges from adaptive responses of the pyrimidine metabolism network

Up‐regulation of SPINT2/HAI‐2 by Azacytidine in bone marrow mesenchymal stromal cells affects leukemic stem cell survival and adhesion

Meta-analysis of studies with genome sequencing in myelodysplastic syndrome treated with hypomethylating agents

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