Identification of fusion genes and characterization of transcriptome features in T-cell acute lymphoblastic leukemia

T-cell acute lymphoblastic leukemia (T-ALL) is a highly aggressive leukemia that is primarily caused by aberrant activation of the NOTCH1 signaling pathway. Recent studies have revealed that posttranslational modifications, such as ubiquitination, regulate NOTCH1 stability, activity, and localization. However, the specific deubiquitinase that affects NOTCH1 protein stability remains unestablished. Here, we report that ubiquitin-specific protease 7 (USP7) can stabilize NOTCH1. USP7 deubiquitinated NOTCH1 in vivo and in vitro, whereas knockdown of USP7 increased the ubiquitination of NOTCH1. USP7 interacted with NOTCH1 protein in T-ALL cells, and the MATH and UBL domains of USP7 were responsible for this interaction. Depletion of USP7 significantly suppressed the proliferation of T-ALL cells in vitro and in vivo, accompanied by downregulation of the NOTCH1 protein level. Similarly, pharmacologic inhibition of USP7 led to apoptosis of T-ALL cells. More importantly, we found that USP7 was significantly upregulated in human T-ALL cell lines and patient samples, and a USP7 inhibitor exhibited cell cytotoxicity toward primary T-ALL cells, indicating the clinical relevance of these findings. Overall, our results demonstrate that USP7 is a novel deubiquitinase that stabilizes NOTCH1. Therefore, USP7 may be a promising therapeutic target in the currently incurable T-ALL.

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“…38,49,50 The role of USP7 in these patients remains enigmatic. Possibly, USP7 may function as a tumor suppressor.…”

Section: Discussionmentioning

confidence: 99%

USP7 deubiquitinates and stabilizes NOTCH1 in T-cell acute lymphoblastic leukemia

Shan

Xiao

et al. 2018

Sig Transduct Target Ther

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“…Nonsilent Sequence Mutation Profile. We next analyzed nonsilent sequence variants in available whole exome sequencing (WES) and RNA-seq data, based on in-house analysis criteria from previous studies (6,8,11,13). We identified 44 genes that were recurrently mutated in at least 1% of the cases (12/1,223 cases).…”

Section: Identification Of Bcp All Subgroups With Distinctive Gene Exmentioning

confidence: 99%

Transcriptional landscape of B cell precursor acute lymphoblastic leukemia based on an international study of 1,223 cases

Dai

Lilljebjörn

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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224

318

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Most B cell precursor acute lymphoblastic leukemia (BCP ALL) can be classified into known major genetic subtypes, while a substantial proportion of BCP ALL remains poorly characterized in relation to its underlying genomic abnormalities. We therefore initiated a large-scale international study to reanalyze and delineate the transcriptome landscape of 1,223 BCP ALL cases using RNA sequencing. Fourteen BCP ALL gene expression subgroups (G1 to G14) were identified. Apart from extending eight previously described subgroups (G1 to G8 associated with MEF2D fusions, TCF3–PBX1 fusions, ETV6–RUNX1–positive/ETV6–RUNX1–like, DUX4 fusions, ZNF384 fusions, BCR–ABL1/Ph–like, high hyperdiploidy, and KMT2A fusions), we defined six additional gene expression subgroups: G9 was associated with both PAX5 and CRLF2 fusions; G10 and G11 with mutations in PAX5 (p.P80R) and IKZF1 (p.N159Y), respectively; G12 with IGH–CEBPE fusion and mutations in ZEB2 (p.H1038R); and G13 and G14 with TCF3/4–HLF and NUTM1 fusions, respectively. In pediatric BCP ALL, subgroups G2 to G5 and G7 (51 to 65/67 chromosomes) were associated with low-risk, G7 (with ≤50 chromosomes) and G9 were intermediate-risk, whereas G1, G6, and G8 were defined as high-risk subgroups. In adult BCP ALL, G1, G2, G6, and G8 were associated with high risk, while G4, G5, and G7 had relatively favorable outcomes. This large-scale transcriptome sequence analysis of BCP ALL revealed distinct molecular subgroups that reflect discrete pathways of BCP ALL, informing disease classification and prognostic stratification. The combined results strongly advocate that RNA sequencing be introduced into the clinical diagnostic workup of BCP ALL.

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“…SLC17A9 activity also plays an important role in maintaining lysosomal physiology and cell viability [9]. Recent studies indicate that overexpression of a short SLC17A9 transcript predicts poor survival in adult patients with T-cell acute lymphoblastic leukemia [10]. And SLC17A9 overexpression in colorectal cancer correlates with poor prognosis [11].…”

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confidence: 99%

High SLC17A9 Expression Correlates with Poor Survival in Gastric Carcinoma

Deng

et al. 2019

Future Oncol.

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Aim: To elucidate the clinicopathological significance and prognostic value of SLC17A9 expression in gastric carcinoma (GC). Methods: SLC17A9 mRNA level and its relationship with TP53 mutation was analyzed. SLC17A9 protein expression was examined by immunohistochemistry in 161 patients. Results: SLC17A9 mRNA and protein expression were higher in GC tissues than in adjacent normal tissues (p < 0.01). SLC17A9 mRNA expression was higher in GC tissues having mutated TP53 than in tissues with wild-type TP53 (p < 0.001). High SLC17A9 expression was also significantly associated with poor overall survival and recurrence-free survival and was also found to be an independent prognostic factor for long-term survival in GC patients.Conclusion: Our results show that SLC17A9 may serve as a potential prognostic biomarker in GC patients.

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Identification of fusion genes and characterization of transcriptome features in T-cell acute lymphoblastic leukemia

Cited by 116 publications

References 33 publications

USP7 deubiquitinates and stabilizes NOTCH1 in T-cell acute lymphoblastic leukemia

USP7 deubiquitinates and stabilizes NOTCH1 in T-cell acute lymphoblastic leukemia

Transcriptional landscape of B cell precursor acute lymphoblastic leukemia based on an international study of 1,223 cases

High SLC17A9 Expression Correlates with Poor Survival in Gastric Carcinoma

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