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HCINAP regulates the DNA-damage response and mediates the resistance of acute myelocytic leukemia cells to therapy.

ABSTRACT: Acute myeloid leukemia (AML) is a genetically heterogeneous malignant disorder of the hematopoietic system, characterized by the accumulation of DNA-damaged immature myeloid precursors. Here, we find that hCINAP is involved in the repair of double-stranded DNA breaks (DSB) and that its expression correlates with AML prognosis. Following DSB, hCINAP is recruited to damage sites where it promotes SENP3-dependent deSUMOylation of NPM1. This in turn results in the dissociation of RAP80 from the damage site and CTIP-dependent DNA resection and homologous recombination. NPM1 SUMOylation is required for recruitment of DNA repair proteins at the early stage of DNA-damage response (DDR), and SUMOylated NPM1 impacts the assembly of the BRCA1 complex. Knockdown of hCINAP also sensitizes a patient-derived xenograft (PDX) mouse model to chemotherapy. In clinical AML samples, low hCINAP expression is associated with a higher overall survival rate in patients. These results provide mechanistic insight into the function of hCINAP during the DNA-damage response and its role in AML resistance to therapy.

SUBMITTER: Xu R

PROVIDER: S-EPMC6707248 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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hCINAP regulates the DNA-damage response and mediates the resistance of acute myelocytic leukemia cells to therapy.

Xu Ruidan R Yu Shuyu S Zhu Dan D Huang Xinping X Xu Yuqi Y Lao Yimin Y Tian Yonglu Y Zhang Jinfang J Tang Zefang Z Zhang Zemin Z Yi Jing J Zhu Hong-Hu HH Zheng Xiaofeng X

Nature communications 20190823 1

Acute myeloid leukemia (AML) is a genetically heterogeneous malignant disorder of the hematopoietic system, characterized by the accumulation of DNA-damaged immature myeloid precursors. Here, we find that hCINAP is involved in the repair of double-stranded DNA breaks (DSB) and that its expression correlates with AML prognosis. Following DSB, hCINAP is recruited to damage sites where it promotes SENP3-dependent deSUMOylation of NPM1. This in turn results in the dissociation of RAP80 from the dama ...[more]

PMID: 31444354

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Project description:BackgroundAcute myeloid leukemia (AML) is the most common acute leukemia in adults, with a median age of 68 in clinical diagnosis. About 60% patients are over 60 years old. There are various treatment options for AML patients. But for elderly patients, the complete remission rates are disappointing due to genetic, molecular, and age-related factors. Development of next-generation sequencing technologies makes it possible to seek individual strategies for patients in different ages. This study analyzed transcriptome profiles in platelets of AML patients in different ages for the first time.MethodsPlatelet RNA sequencing in AML of ten elderly and seven young patients were performed with Illumina TruSeq Stranded mRNA library Prep Kit and Illumina HiSeq4000 sequencing instrument. With the FASTQ sequencing data obtained, statistical analyses between elderly with young AML patients were analyzed by R program. GO and KEGG enrichment analyses were performed via R package clusterProfiler. TOP 10 down-regulated/up-regulated genes in elderly patients compared to young patients were selected with the threshold of |L2FC| > 2 and padj ≤ 0.0001. The down-regulated gene ATF4 was chosen by GSEA analysis and ROC analysis with AUC > 0.95.ResultsWe found 3059 genes with differential transcript levels (GDTLs) in AML patients of different age. Among them, 2048 genes are down-regulated and 651 genes are up-regulated in elderly patients. We found that gene transcript profiles in elderly patients is obviously different from those in young patients, including a collection of down-regulated genes related to proteins processing in endoplasmic reticulum and immunity. We further identified that genes of pathway in cancer and mitogen activated protein kinase (MAPK) pathway, involved in natural immunity and metabolism, are significantly down-regulated in elderly patients. Among all screened genes with decreased transcript levels, we believe that activating transcription factor 4 (ATF4) is a biomarker indicating different chemotherapy strategies for elderly patients.ConclusionsIn summary, gene transcript profiles are different in platelets of elderly and young AML patients. And ATF4 can be a useful biomarker indicating different chemotherapy strategies for AML patients with different ages.

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HCINAP regulates the DNA-damage response and mediates the resistance of acute myelocytic leukemia cells to therapy.

Publications

hCINAP regulates the DNA-damage response and mediates the resistance of acute myelocytic leukemia cells to therapy.

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