Candidate driver genes involved in genome maintenance and DNA repair in Sézary syndrome

Woollard, Wesley J.; Pullabhatla, Venu; Lorenc, Anna; Patel, Varsha M.; Butler, Rosie M.; Bayega, Anthony; Begum, Nelema; Bakr, Farrah; Dedhia, Kiran; Fisher, Joshua N. B.; Aguilar-Duran, Silvia; Flanagan, Charlotte E.; Ghasemi, Aria A.; Hoffmann, Ricarda M.; Castillo-Mosquera, Nubia; Nuttall, Elisabeth A.; Paul, Arisa; Roberts, Ceri A.; Solomonidis, Emmanouil G; Tarrant, Rebecca L.; Yoxall, Antoinette; Beyers, Carl; Ferreira, Sandra Reis; Tosi, Isabella; Simpson, Michael A.; Rinaldis, Emanuele de; Mitchell, Tracey; Whittaker, Sean

doi:10.1182/blood-2016-02-699843

Cited by 96 publications

(106 citation statements)

References 89 publications

Supporting

Mentioning

101

Contrasting

Order By: Relevance

“…Therefore, we cannot conclude that HAT inactive-mutation is a general major cause of HDAC activation in CTCL. Another possibility is that there may be a critical novel cascade that regulates HDACs downstream of these oncogenic products, because there are several active mutations of the oncogenic transcription factors in CTCL [39]. Indeed, it has been demonstrated that the Myc transcription factor, which is frequently dysregulated in almost all advanced cancers, has the potential to recruit HDAC3 in mantle cell lymphoma [40].…”

Section: Discussionmentioning

confidence: 99%

Histone deacetylase inhibitors inhibit metastasis by restoring a tumor suppressive microRNA-150 in advanced cutaneous T-cell lymphoma

et al. 2016

View full text Add to dashboard Cite

Tumor suppressive microRNA (miR)-150 inhibits metastasis by combining with the C-C chemokine receptor 6 (CCR6) “seed sequence” mRNA of the 3′-untranslated region (3′-UTR) in advanced cutaneous T-cell lymphoma (CTCL). Because the histone deacetylase inhibitor (HDACI) vorinostat showed excellent outcomes for treating advanced CTCL, HDACIs may reduce the metastasis of CTCL by targeting miR-150 and/ or CCR6. To examine whether these candidate molecules are essential HDACI targets in advanced CTCL, we used the My-La, HH, and HUT78 CTCL cell lines for functional analysis because we previously demonstrated that their xenografts in NOD/Shi-scid IL-2γnul mice (CTCL mice) induced multiple metastases. We found that pan- HDACIs (vorinostat and panobinostat) inhibited the migration of CTCL cells and downregulated CCR6. The miRNA microarray analysis against CTCL cell lines demonstrated that these pan-HDACIs commonly upregulated 161 miRNAs, including 34 known tumor suppressive miRNAs such as miR-150. Although 35 miRNAs possessing the CCR6 “seed sequence” were included in these 161 miRNAs, miR-150 and miR-185-5p were downregulated in CTCL cells compared to in normal CD4+ T-cells. The transduction of 12 candidate miRNAs against CTCL cells revealed that miR-150 most efficiently inhibited their migration capabilities and downregulated CCR6. Quantitative reverse transcriptase-polymerase chain reaction demonstrated that miR-150 was downregulated in advanced but not early CTCL primary cases. Finally, we injected miR-150 or siCCR6 into CTCL mice and found that mouse survival was significantly prolonged. These results indicate that miR-150 and its target, CCR6, are essential therapeutic targets of pan-HDACIs in advanced CTCL with metastatic potential.

show abstract

Section: Discussionmentioning

confidence: 99%

Histone deacetylase inhibitors inhibit metastasis by restoring a tumor suppressive microRNA-150 in advanced cutaneous T-cell lymphoma

et al. 2016

View full text Add to dashboard Cite

show abstract

“…To this end, a strong correlation was found between p53 functional status and clinical outcomes in lymphoma, such as mortality or resistance to chemotherapy (8, 9). TP53 may be mutated in a proportion of patients with another type of CTCL, Sezary syndrome, but mutations are not predictive for the course of the disease (10). Less is known about TP53 gene status in MF.…”

Section: Introductionmentioning

confidence: 99%

TP53 Gene Status Affects Survival in Advanced Mycosis Fungoides

et al. 2016

View full text Add to dashboard Cite

TP53 is frequently mutated in different types of neoplasms including leukemia and lymphomas. Mutations of TP53 have also been reported in mycosis fungoides (MF), the most common type of cutaneous lymphoma. However, little is known about the frequency, spectrum of mutations, and their prognostic significance in MF. In this study, we have optimized the protocol for Sanger sequencing of TP53 using DNA extracted from archival paraffin-embedded biopsies. Of 19 samples from patients with stage IIB MF or higher, 31% harbored mutations in TP53. Overall survival of the patients with mutated TP53 was significantly shorter than median survival in the age- and stage-matched patients treated in our Institution. Distribution of mutations was heterogenous in TP53 exons; however, C > T transitions were common suggesting the causal role of ultraviolet radiation. We propose that TP53 mutation status would be useful for risk stratification of patients with advanced MF.

show abstract

“…[2][3][4][5][6][7][8] These studies have now confirmed, expanded, and functionally validated many of the genetic aberrations detected by aCGH in MF/SS, a broad and diverse spectrum that include genes associated with T-cell receptor (TCR) signaling, activation of NF-kB, JAK/STAT signaling, chromatin remodeling, and DNA damage response. However, despite a significant degree of overlap, there was great variability in the identity and frequency of alterations at putative driver genes across studies.…”

mentioning

confidence: 72%

Expanding and expounding the genomic map of CTCL

Mishra

Porcu

2017

Blood

View full text Add to dashboard Cite

Candidate driver genes involved in genome maintenance and DNA repair in Sézary syndrome

Abstract: Key Points Aberrations in genome maintenance and DNA repair genes including POT1 occur at a high frequency in Sézary syndrome. Candidate driver genes and affected pathways in Sézary syndrome show extensive heterogeneity but overlap with other mature T-cell lymphomas.

Cited by 96 publications

References 89 publications

Histone deacetylase inhibitors inhibit metastasis by restoring a tumor suppressive microRNA-150 in advanced cutaneous T-cell lymphoma

Histone deacetylase inhibitors inhibit metastasis by restoring a tumor suppressive microRNA-150 in advanced cutaneous T-cell lymphoma

TP53 Gene Status Affects Survival in Advanced Mycosis Fungoides

Expanding and expounding the genomic map of CTCL

Contact Info

Product

Resources

About