Mycosis Fungoides (MYCF)

Overview

Mycosis fungoides (MYCF) is the most common form of cutaneous T-cell lymphoma (CTCL), an indolent CD4+ skin-homing T-cell malignancy that progresses from patch/plaque stage to tumor stage and can advance to systemic involvement. It sits within the Mature T and NK Neoplasms (MTNN) branch of OncoTree (parent: MTNN). Histologically it is defined by epidermotropic atypical T lymphocytes; molecular features include somatic mutations in epigenetic regulators (KMT2D, KMT2C, SMARCA4), TCR/MAPK/JAK-STAT signaling genes (MAPK1, BRAF, STAT3), and generally fewer copy-number alterations than the related Sézary syndrome.

Cohorts in the corpus

  • ctcl_columbia_2015 — whole-exome sequencing of 8 mycosis fungoides tumor-normal pairs (skin biopsies as tumor; buccal swab as germline) among 42 CTCL patients profiled PMID:26551667.

Recurrent alterations

  • Whole-exome sequencing of 8 mycosis fungoides samples (median 62 non-synonymous somatic mutations/sample, range 2–419) identified mutations in epigenetic regulators (KMT2D p.Gln2418, KMT2C p.Gly1246, SMARCA4 p.Arg251Lys) and TCR/MAPK signaling genes (MAPK1 p.Glu322Ala/p.Glu322Lys, STAT3 p.Tyr640Phe in 2 cases); mycosis fungoides had markedly fewer copy-number alterations than Sézary syndrome (median 1 CNA vs 21) PMID:26551667.
  • MAPK1 E322K/E322A activating alleles validated to drive elevated ERK1/2 activation in transfected cells PMID:26551667.
  • STAT3 p.Tyr640Phe activating mutation observed in two mycosis fungoides cases PMID:26551667.

Subtypes

  • Mycosis fungoides and Sézary syndrome are the two dominant CTCL subtypes analyzed in the da Silva Almeida et al. cohort; mycosis fungoides has fewer somatic copy-number alterations and a different mutation spectrum (MAPK1/STAT3 prominent) compared with Sézary syndrome (TP53/RB1/PTEN deletions prominent) PMID:26551667.

Therapeutic landscape

  • Broad CTCL cell-line sensitivity to bortezomib (proteasome inhibitor) and Mi-2 (NFκB inhibitor) regardless of genotype, implicating convergent NFκB activation as a therapeutic vulnerability PMID:26551667.
  • tofacitinib and ruxolitinib (JAK inhibitors) active in JAK3-mutant CTCL lines; JAK3/STAT3/SH2B3 genotyping proposed to stratify patients for JAK-inhibitor trials PMID:26551667.

Sources

  • PMID:26551667 — da Silva Almeida et al., whole-exome sequencing of 42 CTCL patients (25 Sézary syndrome, 8 mycosis fungoides).

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