Cryptic and atypical <scp>KMT2A‐USP2</scp> and <scp>KMT2A‐USP8</scp> rearrangements identified by mate pair sequencing in infant and childhood leukemia

Blackburn, Patrick R.; Smadbeck, James B.; Znoyko, Iya; Webley, Matthew; Pitel, Beth A.; Vasmatzis, George; Xu, Xinjie; Greipp, Patricia T.; Hoppman, Nicole L.; Ketterling, Rhett P.; Baughn, Linda B.; Lindsey, Kathryn; Schandl, Cynthia A.; Wolff, Daynna J.; Peterson, Jess F.

doi:10.1002/gcc.22842

Cited by 9 publications

(8 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Gene fusion detection in a diagnostic setting poses several challenges: (1) specific gene fusions may be rare, [7][8][9] (2) breakpoints may be atypical, [10][11][12][13] and (3) fusion partners may be promiscuous. 14 Both reverse transcriptase polymerase chain reaction (RT-PCR)based assays and fluorescence in situ hybridization (FISH) assays using break-apart probes are a sensitive, but time-consuming method to detect chromosomal rearrangements.…”

Section: Introductionmentioning

confidence: 99%

Improved Gene Fusion Detection in Childhood Cancer Diagnostics Using RNA Sequencing

Hehir-Kwa

Koudijs

Verwiel

et al. 2022

JCO Precision Oncology

View full text Add to dashboard Cite

PURPOSE Gene fusions play a significant role in cancer etiology, making their detection crucial for accurate diagnosis, prognosis, and determining therapeutic targets. Current diagnostic methods largely focus on either targeted or low-resolution genome-wide techniques, which may be unable to capture rare events or both fusion partners. We investigate if RNA sequencing can overcome current limitations with traditional diagnostic techniques to identify gene fusion events. METHODS We first performed RNA sequencing on a validation cohort of 24 samples with a known gene fusion event, after which a prospective pan-pediatric cancer cohort (n = 244) was tested by RNA sequencing in parallel to existing diagnostic procedures. This cohort included hematologic malignancies, tumors of the CNS, solid tumors, and suspected neoplastic samples. All samples were processed in the routine diagnostic workflow and analyzed for gene fusions using standard-of-care methods and RNA sequencing. RESULTS We identified a clinically relevant gene fusion in 83 of 244 cases in the prospective cohort. Sixty fusions were detected by both routine diagnostic techniques and RNA sequencing, and one fusion was detected only in routine diagnostics, but an additional 24 fusions were detected solely by RNA sequencing. RNA sequencing, therefore, increased the diagnostic yield by 38%-39%. In addition, RNA sequencing identified both gene partners involved in the gene fusion, in contrast to most routine techniques. For two patients, the newly identified fusion by RNA sequencing resulted in treatment with targeted agents. CONCLUSION We show that RNA sequencing is sufficiently robust for gene fusion detection in routine diagnostics of childhood cancers and can make a difference in treatment decisions.

show abstract

Section: Introductionmentioning

confidence: 99%

Improved Gene Fusion Detection in Childhood Cancer Diagnostics Using RNA Sequencing

Hehir-Kwa

Koudijs

Verwiel

et al. 2022

JCO Precision Oncology

View full text Add to dashboard Cite

show abstract

“…The Mitelman database of chromosome aberrations and gene fusions in cancer has documented 14 chimeric genes involving USP8, including a fusion between USP8 and lysine methyltransferase 2A (KMT2A) in B-cell lineage acute lymphoplastic leukemia. The KMT2A::USP8 chimera was generated by chromosomal translocation t(11;15)(q23;q21) (51,52). The genomic breakpoints occurred within introns 20 and 12 of KMT2A and USP8 (NM_005154), respectively.…”

Section: Discussionmentioning

confidence: 99%

Fusion of Platelet Derived Growth Factor Receptor Alpha (PDGFRA) With Ubiquitin Specific Peptidase 8 (USP8) in a Calcified Chondroid Mesenchymal Neoplasm Harboring t(4;15)(q12;q21) as a Sole Aberration

PANAGOPOULOS,

ANDERSEN,

GORUNOVA

et al. 2024

Cancer Genomics Proteomics

View full text Add to dashboard Cite

Background/Aim: The term "calcified chondroid mesenchymal neoplasm" was introduced in 2021 to describe a group of tumors characterized by various morphological features, including the formation of cartilage or chondroid matrix. These tumors frequently carry chimeric genes where the 5´-end partner gene is fibronectin 1 and the 3´-end partner gene codes for receptor tyrosine kinase. Our study explores fusion of the genes platelet-derived growth factor receptor alpha (PDGFRA) and ubiquitin-specific peptidase 8 (USP8) in calcified chondroid mesenchymal neoplasm. Case Report: Genetic investigations were conducted on a tumor located in the leg of a 71-year-old woman. G-banding analysis of short-term cultured tumor cells revealed the karyotype 46,XX,t(4;15)(q12;q21)[6]/46,XX [4]. RNA sequencing detected in-frame PDGFRA::USP8 and USP8::PDGFRA chimeric transcripts, which were validated by RT-PCR/Sanger sequencing. The PDGFRA::USP8 chimeric protein is predicted to have cell membrane location and functions as a chimeric ubiquitinyl hydrolase. The USP8::PDGFRA protein was predicted to be nuclear and function as a positive regulator of cellular metabolic process. Conclusion: We report, for the first time, a calcified chondroid mesenchymal neoplasm carrying a balanced t(4;15)(q12;q21) chromosomal translocation, resulting in the generation of both PDGFRA::USP8 and USP8::PDGFRA chimeras. The PDGFRA::USP8 protein is located on the cell membrane and functions as a chimeric ubiquitinyl hydrolase, activated by PDGFs. Conversely, USP8::PDGFRA is a nuclear protein regulating metabolic processes.

show abstract

“…The translocation of the KMT2A gene produces a KMT2A fusion protein that directly binds to DNA and upregulates gene transcription, leading to the development of acute myeloid leukemia (AML) in infants and children ( 164 , 165 ). USP2 serves as a chaperone gene for KMT2A and the poor clinical prognosis of children with KMT2A - USP2 -positive AML has been associated with the aberrant expression of USP2 ( 166 – 168 ). In a prospective study, Meyer et al ( 169 ) reported that a very small number of patients with acute leukemia have rearranged USP2 and USP8 genes and that the conserved region of the deubiquitinating enzyme ‘UCH-domain’ fuses to an extended 5´-MLL portion, which formed the fusion proteins MLL-USP2 and MLL-USP8.…”

Section: Targeting Usp2 For Cancer Therapymentioning

confidence: 99%

Targeting the deubiquitinase USP2 for malignant tumor therapy (Review)

Zhang,

Guo,

Zhang

et al. 2023

Oncol Rep

View full text Add to dashboard Cite

The ubiquitin-proteasome system is a major degradation pathway for >80% of proteins in vivo. Deubiquitylases, which remove ubiquitinated tags to stabilize substrate proteins, are important components involved in regulating the degradation of ubiquitinated proteins. In addition, they serve multiple roles in tumor development by participating in physiological processes such as protein metabolism, cell cycle regulation, DNA damage repair and gene transcription. The present review systematically summarized the role of ubiquitin-specific protease 2 (USP2) in malignant tumors and the specific molecular mechanisms underlying the involvement of USP2 in tumor-associated pathways. USP2 reverses ubiquitin-mediated degradation of proteins and is involved in aberrant proliferation, migration, invasion, apoptosis and drug resistance of tumors. Additionally, the present review summarized studies reporting on the use of USP2 as a therapeutic target for malignancies such as breast, liver, ovarian, colorectal, bladder and prostate cancers and glioblastoma and highlights the current status of pharmacological research on USP2. The clinical significance of USP2 as a therapeutic target for malignant tumors warrants further investigation. Contents 1. Introduction 2. Role of USP2 in the biological behavior of malignant tumors 3. Targeting USP2 for cancer therapy 4. Pharmacological studies of USP2 5. Concluding remarks and potential future directions

show abstract

Cryptic and atypical KMT2A‐USP2 and KMT2A‐USP8 rearrangements identified by mate pair sequencing in infant and childhood leukemia

Cited by 9 publications

References 21 publications

Improved Gene Fusion Detection in Childhood Cancer Diagnostics Using RNA Sequencing

Improved Gene Fusion Detection in Childhood Cancer Diagnostics Using RNA Sequencing

Fusion of Platelet Derived Growth Factor Receptor Alpha (PDGFRA) With Ubiquitin Specific Peptidase 8 (USP8) in a Calcified Chondroid Mesenchymal Neoplasm Harboring t(4;15)(q12;q21) as a Sole Aberration

Targeting the deubiquitinase USP2 for malignant tumor therapy (Review)

Contact Info

Product

Resources

About