Chidamide inhibits the NOTCH1-MYC signaling axis in T-cell acute lymphoblastic leukemia

doi:10.1007/s11684-021-0877-y

Front. Med.

2022, Vol. 16

Issue (3) : 442-458 https://doi.org/10.1007/s11684-021-0877-y

RESEARCH ARTICLE

Chidamide inhibits the NOTCH1-MYC signaling axis in T-cell acute lymphoblastic leukemia

Mengping Xi^1,², Shanshan Guo^1,², Caicike Bayin^1,², Lijun peng^1,², Florent Chuffart^2,³, Ekaterina Bourova-Flin^2,³, Sophie Rousseaux^2,³(

), Saadi Khochbin^2,³(

), Jian-Qing Mi^1,²(

), Jin Wang^1,²(

)

¹. Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
². Pôle de Recherches Sino-Français en Science du Vivant et Génomique, Shanghai 200025, China
³. CNRS UMR 5309/INSERM U1209/Université Grenoble Alpes/Institute for Advanced Biosciences, 38706 La Tronche, France

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Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is one of the most dangerous hematological malignancies, with high tumor heterogeneity and poor prognosis. More than 60% of T-ALL patients carry NOTCH1 gene mutations, leading to abnormal expression of downstream target genes and aberrant activation of various signaling pathways. We found that chidamide, an HDAC inhibitor, exerts an antitumor effect on T-ALL cell lines and primary cells including an anti-NOTCH1 activity. In particular, chidamide inhibits the NOTCH1-MYC signaling axis by down-regulating the level of the intracellular form of NOTCH1 (NICD1) as well as MYC, partly through their ubiquitination and degradation by the proteasome pathway. We also report here the preliminary results of our clinical trial supporting that a treatment by chidamide reduces minimal residual disease (MRD) in patients and is well tolerated. Our results highlight the effectiveness and safety of chidamide in the treatment of T-ALL patients, including those with NOTCH1 mutations and open the way to a new therapeutic strategy for these patients.

Keywords T-cell acute lymphoblastic leukemia HDAC inhibitor chidamide NOTCH1 MYC ubiquitination

Corresponding Author(s): Sophie Rousseaux,Saadi Khochbin,Jian-Qing Mi,Jin Wang

Just Accepted Date: 02 August 2021 Online First Date: 19 October 2021 Issue Date: 18 July 2022

Cite this article:

Mengping Xi,Shanshan Guo,Caicike Bayin, et al. Chidamide inhibits the NOTCH1-MYC signaling axis in T-cell acute lymphoblastic leukemia[J]. Front. Med., 2022, 16(3): 442-458.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-021-0877-y
https://academic.hep.com.cn/fmd/EN/Y2022/V16/I3/442

Fig.1 Chidamide inhibits cell viability in T-ALL patients’ primary cells with or without NOTCH1 mutation. Cell viability after treatment with increasing concentrations of chidamide (as indicated) in primary cells from T-ALL patients with NOTCH1 mutation (A–C) or without NOTCH1 mutation (D–F). The three curves respectively in blue, red and black correspond to different durations of treatment of 24, 48, and 72 h.

Fig.2 Chidamide treatment induces an arrest of the cell cycle in G0/G1 phase. (A) In Jurkat and MOLT-4 cell lines cell viability is significantly inhibited by a treatment with chidamide at concentrations above 0.3 to 3 μmol/L. (B) HDAC activity in chidamide-treated cells is significantly reduced compared to untreated cells of both cell lines. HDAC activity in control and chidamide-treated cells were measured by absorbance at 450 nm. (C) The proportion of cells at G0/G1 cell cycle stage is increased after treatment for 48 h with increased concentrations of chidamide (as indicated). * P<0.05, **P<0.01, ****P<0.0001. (D) p21 increases and cyclin D1 decreases as a function of chidamide concentration in chidamide-treated cells of both Jurkat and MOLT-4 cell lines. Western blot detecting p21 and cyclin D1 in cells treated with different concentrations of chidamide (as indicated) for 48 h.

Fig.3 Chidamide induces apoptosis in NOTCH1 mutant T-ALL cell lines by activating the endogenous apoptotic pathway. (A) Cell apoptosis increases as a function of chidamide concentration and treatment duration. * P<0.05, **P<0.01, ****P<0.0001. (B) Western blot detecting caspase-3, 8, 9, and PARP in Jurkat and MOLT-4 cells treated with chidamide at the indicated concentrations for 48 h. (C) Western blot detecting anti-apoptotic molecule (Bcl-2 and Bcl-xL) and pro-apoptotic molecule (Bim) in Jurkat and MOLT-4 cells treated with chidamide at the indicated concentrations for 48 h.

Fig.4 Chidamide inhibits NOTCH1-MYC signaling axis in both Jurkat and MOLT-4 cell lines by increasing proteasome dependent degradation of both proteins. (A–C) Chidamide does not affect the transcription of NOTCH1 and MYC in Jurkat cells, but inhibits the transcription of NOTCH1 in MOLT-4 cells (P<0.01) as shown in the RNAseq data analysis (A) or RT-QPCR experiments (B and C). (D) Western blot detecting NICD1 and MYC in Jurkat and MOLT-4 cells treated with chidamide at the indicated concentrations for 48 h.

Fig.5 Chidamide promotes the degradation of NOTCH1 and MYC via the proteasome pathway in both Jurkat (A and C) and MOLT-4 (B and D) cells. (A and B) The chidamide-treated and untreated control cells were cultured under the same culture conditions for 24 h. 10 μg/mL of CHX was added at the same time to chidamide-treated and control cells and Western blots were performed after the indicated periods of time to detect NICD1 and MYC. The degradation rate of NICD1 and MYC proteins in the chidamide-treated cells was faster than that in the untreated control cells. (C and D) The chidamide-treated and untreated control cells were cultured under the same culture conditions for 24 h. 10 μmol/L of MG132 was added at the same time to both chidamide-treated and untreated cells and Western blots were performed after the indicated periods of time to detect NICD1 and MYC. MG132 increased the levels of NICD1 and MYC proteins in both chidamide-treated and untreated cells, suggesting that the two proteins were prevented from being degraded by the proteasome pathway. (E) The proteasome-dependent degradation of both NICD1 and MYC requires their ubiquitination. Immunoprecipitation experiments followed by immunodetection of ubiquitination show that the ubiquitination levels of NICD1 and MYC proteins in the chidamide-treated cells are were significantly increased compared to those in non-treated cells.

Fig.6 GSEA analysis in Jurkat and MOLT-4 cell lines. (A–C) Chidamide has a “HDAC inhibitor-like” effect on gene expression in Jurkat and MOLT-4 cell lines. Proliferation HDAC dependent genes are downregulated by chidamide (A), whereas genes normally downregulated by HDAC1 or HDAC2 are overexpressed in chidamide-treated cells (B and C). (D) Chidamide causes significant downregulation of genes involved in cell cycle. (E–G) Chidamide treatment causes a significant upregulation of a set of genes anti-regulated with NOTCH1 (genes whose expressions are anti-correlated with NOTCH1 expression in ALL samples, with Pearson and Spearman coefficients<–0.6) in the two cell lines Jurkat (E) and MOLT-4 (F) respectively, or considering both cell lines (G). (H and I) MYC target genes are significantly downregulated in chidamide-treated Jurkat and MOLT-4 cells as exemplified here with these two genesets from the “hallmark” category of MsigDB.

Fig.7 Chidamide combined with chemotherapy regimens decreases MRD in patient primary cells with NOTCH1 mutation. The black icons mean that the patient only received chemotherapy regimens (Hyper-CVAD-A, alternating with Hyper-CVAD-B monthly). The red icons mean that the patient received chidamide combined with Hyper-CVAD-A, alternating with chidamide combined with Hyper-CVAD-B monthly. (A) Patient 2 was a relapsed patient with NOTCH1 mutations, this patient remained in a disease-free state after taking chidamide combined with chemotherapy regimens. (B) Patient 3, a newly diagnosed T-ALL carrying NOTCH1 mutations, showed a decrease of MRD below 0.01% after chidamide combined with chemotherapy regimens. (C) Patient 4 was also a newly diagnosed patient carrying NOTCH1 mutations, and showed a decrease of MRD after chidamide combined with chemotherapy regimens.

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