Frequent CTLA4-CD28 gene fusion in diverse types of T-cell lymphoma

We read with interest the comments raised by Gong et al.1 on our recently published study, 2 and appreciate these important and critical remarks.We agree that contamination is a potential important problem with polymerase chain reaction (PCR)-based work. To avoid the possibility of contamination, we confirmed our data before completion of our manuscript. We performed the PCR experiment using new experimental reagents at a different laboratory. We also repeated the PCR to detect the fusion using two different set of primers, the new primer set producing longer amplicons than the old primer set. All these efforts produced identical results, confirming that our samples were not contaminated by PCR amplicons.As the direct fusion of one exon of CTLA4 to an exon of CD28 is less likely than fusion breakpoints within the introns, we confirmed direct fusion of the two exons at the genomic DNA level with other experiments before submitting our manuscript. As shown in Figure 1, direct fusion of exon 3 of CTLA4 to exon 4 of CD28 was confirmed by PCR using primers from intron 2 of CTLA4 and the 3' region of CD28 using genomic DNA from formalin-fixed, paraffin-embedded samples. PCR products were validated by Sanger sequencing. DNA from normal blood was used as a control as well as no template controls. These data confirm that the fusion is present at the DNA level and is not the result of contamination.We also tried to perform fluorescent in situ hybridization experiments. However it was difficult to design probes which can distinguish the fusion segment because the CD28 and CTLA4 genes are located very close to each other. As shown in our manuscript 2 in Online Supplementary Figure S5, the result was not helpful for delineating the fusion signal from the normal signal.

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“…We read with interest the comments raised by Gong et al 1 on our recently published study, 2 and appreciate these important and critical remarks.…”

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confidence: 84%

“…However it was difficult to design probes which can distinguish the fusion segment because the CD28 and CTLA4 genes are located very close to each other. As shown in our manuscript 2 in Online Supplementary Figure S5, the result was not helpful for delineating the fusion signal from the normal signal. LETTERS TO THE EDITOR Figure 1.…”

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confidence: 86%

Author reply to Comment on: Frequent CTLA4-CD28 gene fusion in diverse types of T-cell lymphoma, by Yoo et al.

Yoo

Kim

et al. 2016

Haematologica

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“…In this work, both transduced murine CD4 and CD8 T cells were found to be important for DLI success. Interestingly, a recent study reported the "natural" occurrence of CTLA4-CD28 gene fusion in diverse types of T-cell lymphoma which can promote cell growth [230]. Further characterization of such kind of fusion (or natural CCR) should be explored.…”

Section: Use Of Chimeric Co-stimulation And/or Switch Receptorsmentioning

confidence: 96%

T-cells “à la CAR-T(e)” – Genetically engineering T-cell response against cancer

Eisenberg

Hoogi

Shamul

et al. 2019

Advanced Drug Delivery Reviews

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“…49 The AITL-specific distribution suggests that CD28 mutations as well as IDH2 mutations may account for specific pathological features of AITL. CTLA4-CD28 fusion genes were reported to be found in 58% of AITL samples, 54 although the actual frequency of the fusion genes is uncertain because of the much lower frequency in another report. 55 ICOS-CD28, another fusion gene involving the CD28 gene, was also described.…”

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confidence: 99%

Recent Progress in the Understanding of Angioimmunoblastic T-cell Lymphoma

Fujisawa

Sakata‐Yanagimoto

2017

JCEH

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Angioimmunoblastic T-cell lymphoma (AITL) has been classified as a subtype of mature T-cell neoplasms. The recent revision of the WHO classification proposed a new category of nodal T-cell lymphoma with follicular helper T (TFH)-cell phenotype, which was classified into three diseases: AITL, follicular T-cell lymphoma, and nodal peripheral T-cell lymphoma with TFH phenotype. These lymphomas are defined by the expression of TFH-related antigens, CD279/PD-1, CD10, BCL6, CXCL13, ICOS, SAP, and CXCR5. Although recurrent mutations in TET2, IDH2, DNMT3A, RHOA, and CD28, as well as gene fusions, such as ITK-SYK and CTLA4-CD28, were not diagnostic criteria, they may be considered as novel criteria in the near future. Notably, premalignant mutations, tumor-specific mutations, and mutations specific to tumor-infiltrating B cells were identified in AITL. Thus, multi-step and multi-lineage genetic events may lead to the development of AITL.

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Frequent CTLA4-CD28 gene fusion in diverse types of T-cell lymphoma

Cited by 71 publications

References 27 publications

Author reply to Comment on: Frequent CTLA4-CD28 gene fusion in diverse types of T-cell lymphoma, by Yoo et al.

Author reply to Comment on: Frequent CTLA4-CD28 gene fusion in diverse types of T-cell lymphoma, by Yoo et al.

T-cells “à la CAR-T(e)” – Genetically engineering T-cell response against cancer

Recent Progress in the Understanding of Angioimmunoblastic T-cell Lymphoma

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