Whole-genome sequencing reveals oncogenic mutations in mycosis fungoides

Abstract

Key Points High-throughput sequencing of MF revealed multiple mutations within epigenetic and cytokine pathways that may drive disease. Pharmacologically targeting the JAK3 pathway in MF results in cell death and may be an effective treatment of this disease.

Mutated JAK kinases and deregulated STAT activity are potential therapeutic targets in cutaneous T-cell lymphoma

“…3,4,[8][9][10] Thus, it has been shown that JAK pseudokinase domains are auto-inhibitory and keep the kinase domain inactive until receptor dimerization stimulates transition to an active state. 11 Molecular analysis of deregulated JAK/STAT signaling has provided a novel rationale for treating human cancers using targeted inhibition of JAK kinases.…”

“…These findings were recently confirmed by an independent group, suggesting that mutations in this pathway may contribute as disease mechanisms in CTCL. 3 Deregulated JAK/STAT signaling is involved in many types of cancer. In fact, somatically acquired genetic alterations of JAK or STAT genes that induce aberrant activation of downstream signaling, via STAT phosphorylation, have been reported in some human hematologic malignancies including T-cell lymphomas.…”

Staphylococcal enterotoxin A (SEA) stimulates STAT3 activation and IL-17 expression in cutaneous T-cell lymphoma

“…13,24 Activating mutations are sufficient to turn STAT3 into a full oncogene in experimental animals, 10 and activating mutations in Janus kinases (JAKs) have been described in other hematologic malignancies. [25][26][27] Recently, activating mutations have also been described in a subset (12.5%) of CTCL patients, 28,29 but it remains unknown what drives aberrant activation of JAK/STAT signaling in the majority of patients. STAT3 activation may become further increased after loss of regulatory control by suppressor of cytokines signaling 3, by protein inhibitor of activated STAT3, and by other tyrosine protein phosphatases.…”

Expanding and expounding the genomic map of CTCL

“…[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.…”

“…However, despite a significant degree of overlap, there was great variability in the identity and frequency of alterations at putative driver genes across studies. For example, some studies identified loss-of-function mutations or deletions of TCF8/ZEB1 in 56% to 65% of cases, 2,5,6 whereas others did not. 4 By compiling the published NGS data from 220 MF/SS patients, and subjecting them to a uniform statistical analysis, Park et al were able to achieve a sample size adequate to identify 55 putative driver genes, including novel mutations at 17 genes, 5 of which had never been involved in cancer.…”