Demethylation and Up-Regulation of an Oncogene after Hypomethylating Therapy

Liu, Yao‐Chung; Kwon, Junsu; Fabiani, Emiliano; Xiao, Zhijian; Liu, Yanjing V.; Follo, Matilde Y.; Liu, Jinqin; Huang, Huijun; Gao, Chong; Li, Jun; Falconi, Giulia; Valentini, Lia; Gurnari, Carmelo; Finelli, Carlo; Cocco, Lucio; Liu, Jin-Hwang; Jones, Alexander; Yang, Junyu; Yang, Henry; Thoms, Julie A.I.; Unnikrishnan, Ashwin; Pimanda, John E.; Pan, Rongqing; Bassal, Mahmoud A.; Voso, Maria Teresa; Tenen, Daniel G.; Chai, Li

doi:10.1056/nejmoa2119771

Cited by 27 publications

(25 citation statements)

References 39 publications

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“…Moreover, a recent study by Liu, Y.C., et al revealed that HMAs strikingly enhance the expression of SALL4 (a welldescribed oncogene) by demethylation in its CpG island within the 5' untranslated region a group of MDS. This demethylating effect on SALL4 was then confirmed to associate with an inferior clinical outcome (34)(35)(36).…”

Section: Discussionmentioning

confidence: 90%

Dynamics of PD-1 expression are associated with treatment efficacy and prognosis in patients with intermediate/high-risk myelodysplastic syndromes under hypomethylating treatment

Geng

Xu²,

Huang³

et al. 2022

Front. Immunol.

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Hypomethylating agents (HMAs) are widely used in patients with higher-risk MDS not eligible for stem cell transplantation. However, the general response rate by HMAs is lesser than 50% in MDS patients, while the relapse rate is high. Emerging evidence indicates that demethylating effects committed by HMAs may facilitate the up-regulation of a range of immune checkpoints or cancer suppressor genes in patients with MDS, among which the programmed death protein 1 (PD-1) and its ligands are demonstrated to be prominent and may contribute to treatment failure and early relapse. Although results from preliminary studies with a limited number of enrolled patients indicate that combined administration of PD-1 inhibitor may yield extra therapeutic benefit in some MDS patients, identifications of this subgroup of patients and optimal timing for the anti-PD-1 intervention remain significant challenges. Dynamics of immune checkpoints and associated predictive values during HMA-treatment cycles remained poorly investigated. In this present study, expression levels of immune checkpoints PD-1 and its ligands PD-L1 and PD-L2 were retrospectively analyzed by quantitative PCR (Q-PCR) in a total of 135 myelodysplastic syndromes (MDS) cohort with higher-risk stratification. The prognostic value of dynamics of these immune checkpoints during HMA cycles was validated in two independent prospective cohorts in our center (NCT01599325 and NCT01751867). Our data revealed that PD-1 expression was significantly higher than that in younger MDS patients (age ≤ 60) and MDS with lower IPSS risk stratification (intermediate risk-1). A significantly up-regulated expression of PD-1 was seen during the first four HMA treatment cycles in MDS patients, while similar observation was not seen concerning the expression of PD-L1 or PD-L2. By utilizing binary logistic regression and receiver operating characteristic (ROC) models, we further identified that higher or equal to 75.9 PD-1 expressions after 2 cycles of HMA treatment is an independent negative prognostic factor in predicting acute myeloid leukemia (AML) transformation and survival. Collectively, our data provide rationales for monitoring the expression of PD-1 during HMA treatment cycles, a higher than 75.9 PD-1 expression may identify patients who will potentially benefit from the combined therapy of HMA and PD-1 inhibitors.

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Section: Discussionmentioning

confidence: 90%

Dynamics of PD-1 expression are associated with treatment efficacy and prognosis in patients with intermediate/high-risk myelodysplastic syndromes under hypomethylating treatment

Geng

Xu²,

Huang³

et al. 2022

Front. Immunol.

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“…To expand the scope of SALL4 targeted therapy in cancer, we explored a sequential combination therapy approach recently. It has been demonstrated that hypomethylating agents (HMA) which are currently used to treat various types of cancers, activate SALL4 through DNA demethylation as a probable side effect [ 18 ]. We started with HMA to prime the SALL4 negative lung cancer cells to become SALL4 positive, therefore, to induce a SALL4-mediated vulnerability in these cells, and then sensitized these cells to the following Entinostat treatment.…”

Section: Sall4 As a Potential Therapeutic Targetmentioning

confidence: 99%

“…The epigenetic modifications also affect SALL4 expression through the CpG island located at the Exon 1/Intron 1 region and reported to be hypomethylated both in embryonic stem cell and cancer cells [ 15 ]. De-methylation of this region can lead to SALL4 activation [ 16 , 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

SALL4: An Intriguing Therapeutic Target in Cancer Treatment

Moein

Tenen

Amabile

et al. 2022

Cells

Self Cite

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Spalt-Like Transcription Factor 4 (SALL4) is a critical factor for self-renewal ability and pluripotency of stem cells. On the other hand, various reports show tight relation of SALL4 to cancer occurrence and metastasis. SALL4 exerts its effects not only by inducing gene expression but also repressing a large cluster of genes through interaction with various epigenetic modifiers. Due to high expression of SALL4 in cancer cells and its silence in almost all adult tissues, it is an ideal target for cancer therapy. However, targeting SALL4 meets various challenges. SALL4 is a transcription factor and designing appropriate drug to inhibit this intra-nucleus component is challenging. On the other hand, due to lack of our knowledge on structure of the protein and the suitable active sites, it becomes more difficult to reach the appropriate drugs against SALL4. In this review, we have focused on approaches applied yet to target this oncogene and discuss the potential of degrader systems as new therapeutics to target oncogenes.

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“…In a recently published study in The New England Journal of Medicine , Liu and colleagues were able to demonstrate that—apart from the anti-leukemic effects previously reported for hypomethylating agents (HMAs)—treatment with these drugs can also lead to demethylation and subsequent upregulation of oncogenes resulting in shorter survival in patients with myelodysplastic syndrome (MDS). 1 …”

mentioning

confidence: 99%

“…First of all, SALL4 is aberrantly expressed in different myeloid neoplasms. 1 , 3 Functionally, it appears to activate the Wnt/β-catenin signaling pathway which resulted in MDS-like phenotypes in a murine model of SALL4 overexpression. 3 Perhaps most importantly, its expression has been shown to depend on the methylation status of the gene.…”

mentioning

confidence: 99%