<i>CEBPA</i> mutants down-regulate AML cell susceptibility to NK-mediated lysis by disruption of the expression of NKG2D ligands, which can be restored by LSD1 inhibition

Li, Meng; Du, Mengbao; Yu, Jian; Qian, Zhiliang; Gao, Yang; Pan, Weiqiang; Zhao, Xiang‐Yu; Wang, Mowang; Li, Huimin; Zheng, Jiaqi; Huang, Qianshuo; Wang, Limengmeng; Xiao, Haowen

doi:10.1080/2162402x.2021.2016158

Cited by 9 publications

(14 citation statements)

References 37 publications

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“…Liu et al revealed that CEBPA, one of the most studied lineage-specific transcription factors in haematopoiesis, might influence the expression of NKG2D; thus, the high endogenous CEBPA-expressing decreased the sensitivity to NK cell cytotoxicity. 24 NKG2D is one of the most critical activating receptors expressed by NK cells and CD8+ αβ+ T cells and binds to MHC Class I chain-related genes (MIC). The binding of NKG2D to MIC protein on the target tumour cells releases the cytotoxicity effect of NK cells.…”

Section: Discussionmentioning

confidence: 99%

Risk factors and survival analysis of human leukocyte antigen loss in relapsed acute myeloid leukaemia/myelodysplastic syndrome patients after allogeneic haematopoietic stem cell transplantation

Zhang,

Zhou

et al. 2024

Br J Haematol

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SummaryTo investigate the clinical characteristics and risk factors of specific human leukocyte antigen loss (HLA loss) in relapsed acute myeloid leukaemia (AML)/myelodysplastic syndrome (MDS) patients after allogeneic haematopoietic stem cell transplantation (allo‐HSCT), and compare the responses of patients with HLA loss relapse with those without HLA loss (non‐HLA loss) to different treatment regimens. Clinical data of traceable patients with AML/MDS after myeloablative allo‐HSCT in our centre between January 2010 and June 2021, who experienced disease relapse after the transplantation, were collected. The patients were divided into the HLA loss relapse group and the non‐HLA loss relapsed group based on HLA loss gene test findings by next‐generation sequencing. The patients' median overall survival (OS) after the relapse were compared, and univariate and multivariate analyses were performed using the Kaplan–Meier survival curve and Cox proportional hazard model to explore the responses to different treatments after relapse. A total of 2359 patients were selected. Retrospective HLA gene loss gene detection was performed for the deoxyribonucleic acid in 179 relapsed patients, including 47 patients in the HLA loss group (27.2%), 126 patients in the non‐HLA loss group (72.8%) and 6 patients were excluded due to a lack of confirmed results. There was no significant statistical difference in the baseline characteristics of patients between the two groups, but as to transplantation‐related characteristics, the donor–recipient relationship and HLA mismatched loci were statistically different between the two groups (both p < 0.001). Multivariate Cox analysis showed that more HLA mismatched loci ≥3 (HR = 3.66; 95% CI: 1.61–8.31; p = 0.002), time (≤6 months) from HSCT to relapse (HR = 7.92; 95% CI: 3.35–18.74; p < 0.001) and donor chimerism (CD3) in bone marrow at relapse (HR = 1.02; 95% CI: 1.00–1.03; p = 0.036) were independent factors affecting HLA loss relapse. The ratio of negative conversion of FLT3‐ITD or CEBPA mutation was significantly lower in patients with post‐transplantation HLA loss relapse than in the non‐HLA loss group (0.0% vs. 45.5%, p = 0.003; 0.0% vs. 80.0%, p = 0.035), with none of the patients with FLT3‐ITD or CEBPA mutation turned negative in the HLA loss group. The number of gene mutations turned negative when relapse in the non‐HLA loss group was remarkably higher than that in the HLA loss group (p = 0.001). Using donor lymphocyte infusion (DLI) could not prolong OS for the HLA loss group (p = 0.42). Nevertheless, second transplantation had a significant positive impact on OS in the HLA loss group (p = 0.017), although only five patients in the HLA loss group underwent second transplantation. However, patients in the non‐HLA loss group using DLI had a relatively longer OS time than those without DLI (p = 0.017). Second transplantation could also prolong OS in the non‐HLA loss group, but the effect was not as significant as in the HLA loss group (p = 0.053). In summary, HLA loss detection is essential for patients with recurrence after transplantation, especially for those with more HLA mismatched loci and non‐sibling donor. Furthermore, the detection of HLA loss has a guiding role in choosing subsequent therapy when relapsed, as secondary transplantation is more suitable than DLI for those with HLA loss.

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Section: Discussionmentioning

confidence: 99%

Risk factors and survival analysis of human leukocyte antigen loss in relapsed acute myeloid leukaemia/myelodysplastic syndrome patients after allogeneic haematopoietic stem cell transplantation

Zhang,

Zhou

et al. 2024

Br J Haematol

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“…AML therapy failure is mostly due to frequent relapses arising from the residual disease, and the immune system is considered crucial for elimination of leukemia cells surviving after chemotherapy and hematopoietic cell transplantation. Compared to solid tumors, AML has a low mutational burden, but several driver mutations with high incidence produce immunogenic peptides 38 and AML is susceptible to attack by both the innate and adaptive immune system. 6 However, multiple molecular mechanisms can mediate immune evasion or active immune suppression.…”

Section: Discussionmentioning

confidence: 99%

NPM1 and DNMT3A mutations are associated with distinct blast immunophenotype in acute myeloid leukemia

et al. 2022

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The immune system is important for elimination of residual leukemic cells during acute myeloid leukemia (AML) therapy. Anti-leukemia immune response can be inhibited by various mechanisms leading to immune evasion and disease relapse. Selected markers of immune escape were analyzed on AML cells from leukapheresis at diagnosis (N = 53). Hierarchical clustering of AML immunophenotypes yielded distinct genetic clusters. In the absence of DNMT3A mutation, NPM1 mutation was associated with decreased HLA expression and low levels of other markers (CLIP, PD-L1, TIM-3). Analysis of an independent cohort confirmed decreased levels of HLA transcripts in patients with NPM1 mutation. Samples with combined NPM1 and DNMT3A mutations had high CLIP surface amount suggesting reduced antigen presentation. TIM-3 transcript correlated not only with TIM-3 surface protein but also with CLIP and PD-L1. In our cohort, high levels of TIM-3/PD-L1/CLIP were associated with lower survival. Our results suggest that AML genotype is related to blast immunophenotype, and that high TIM-3 transcript levels in AML blasts could be a marker of immune escape. Cellular pathways regulating resistance to the immune system might contribute to the predicted response to standard therapy of patients in specific AML subgroups and should be targeted to improve AML treatment.

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“…Human AML cell lines and 32Dcl3 murine myeloid cell line were transduced with recombinant lentiviruses and the plasmids used in this study have been previously described [ 23 ]. Detailed information is described in Supplemental Materials and Methods.…”

Section: Methodsmentioning

confidence: 99%

“…RNA analysis was extracted as previously described [ 23 ]. Specific procedures are described in Supplemental Materials and Methods.…”

Section: Methodsmentioning

confidence: 99%

C/EBPα-p30 confers AML cell susceptibility to the terminal unfolded protein response and resistance to Venetoclax by activating DDIT3 transcription

Du,

Wang,

Liu

et al. 2024

J Exp Clin Cancer Res

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Background Acute myeloid leukemia (AML) with biallelic (CEBPAbi) as well as single mutations located in the bZIP region is associated with a favorable prognosis, but the underlying mechanisms are still unclear. Here, we propose that two isoforms of C/EBPα regulate DNA damage-inducible transcript 3 (DDIT3) transcription in AML cells corporately, leading to altered susceptibility to endoplasmic reticulum (ER) stress and related drugs. Methods Human AML cell lines and murine myeloid precursor cell line 32Dcl3 cells were infected with recombinant lentiviruses to knock down CEBPA expression or over-express the two isoforms of C/EBPα. Quantitative real-time PCR and western immunoblotting were employed to determine gene expression levels. Cell apoptosis rates were assessed by flow cytometry. CFU assays were utilized to evaluate the differentiation potential of 32Dcl3 cells. Luciferase reporter analysis, ChIP-seq and ChIP-qPCR were used to validate the transcriptional regulatory ability and affinity of each C/EBPα isoform to specific sites at DDIT3 promoter. Finally, an AML xenograft model was generated to evaluate the in vivo therapeutic effect of agents. Results We found a negative correlation between CEBPA expression and DDIT3 levels in AML cells. After knockdown of CEBPA, DDIT3 expression was upregulated, resulting in increased apoptotic rate of AML cells induced by ER stress. Cebpa knockdown in mouse 32Dcl3 cells also led to impaired cell viability due to upregulation of Ddit3, thereby preventing leukemogenesis since their differentiation was blocked. Then we discovered that the two isoforms of C/EBPα regulate DDIT3 transcription in the opposite way. C/EBPα-p30 upregulated DDIT3 transcription when C/EBPα-p42 downregulated it instead. Both isoforms directly bound to the promoter region of DDIT3. However, C/EBPα-p30 has a unique binding site with stronger affinity than C/EBPα-p42. These findings indicated that balance of two isoforms of C/EBPα maintains protein homeostasis and surveil leukemia, and at least partially explained why AML cells with disrupted C/EBPα-p42 and/or overexpressed C/EBPα-p30 exhibit better response to chemotherapy stress. Additionally, we found that a low C/EBPα p42/p30 ratio induces resistance in AML cells to the BCL2 inhibitor venetoclax since BCL2 is a major target of DDIT3. This resistance can be overcome by combining ER stress inducers, such as tunicamycin and sorafenib in vitro and in vivo. Conclusion Our results indicate that AML patients with a low C/EBPα p42/p30 ratio (e.g., CEBPAbi) may not benefit from monotherapy with BCL2 inhibitors. However, this issue can be resolved by combining ER stress inducers.

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CEBPA mutants down-regulate AML cell susceptibility to NK-mediated lysis by disruption of the expression of NKG2D ligands, which can be restored by LSD1 inhibition

Cited by 9 publications

References 37 publications

Risk factors and survival analysis of human leukocyte antigen loss in relapsed acute myeloid leukaemia/myelodysplastic syndrome patients after allogeneic haematopoietic stem cell transplantation

Risk factors and survival analysis of human leukocyte antigen loss in relapsed acute myeloid leukaemia/myelodysplastic syndrome patients after allogeneic haematopoietic stem cell transplantation

NPM1 and DNMT3A mutations are associated with distinct blast immunophenotype in acute myeloid leukemia

C/EBPα-p30 confers AML cell susceptibility to the terminal unfolded protein response and resistance to Venetoclax by activating DDIT3 transcription

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