Introduction:
A patient with mycosis fungoides (MF) harboring a PCM1-JAK2 fusion experienced a durable response to ruxolitinib before developing resistance. Here, we detail the case and the molecular profiling of her tumors before and after ruxolitinib resistance.
Methods:
Mutational profiling was performed by whole-exome sequencing (WES). T-cell receptor and gene expression profiling was performed by single-cell RNA sequencing (scRNA-seq) using 10x Genomics Chromium Single Cell 5' Library V3 kit.
Results:
We present a young woman with stage IIB MF recalcitrant to over 10 lines of systemic therapy and radiation. Next-generation sequencing identified a PCM1-JAK2 fusion in a skin tumor, prompting treatment with oral ruxolitinib. She experienced gradual partial improvement, and topical ruxolitinib was added after 4 months to enhance JAK inhibition. By 5 months, a partial response was observed via mSWAT and PET/CT. She remained on ruxolitinib for 19 months before developing resistance. WES of tumor biopsies before and after resistance revealed 24 new coding variants and genomic loss at 12q12, affecting 5 and 103 cancer-associated genes, respectively. The PCM1-JAK2 fusion persisted post-resistance, with no genomic events involving canonical JAK-STAT regulators. Emerging deleterious variants included CHD2 (p.Q395X), TP53BP1 (chr15:43,730,520 A>T), and deletions of ARID2, KMT2D, and SMARCD1. scRNA-seq showed upregulation of T-cell activation (FDR 1x10⁻⁴) and downregulation of JAK-STAT signaling (FDR 3.18x10⁻²) in malignant T cells post-resistance compared to pre-resistance.
Conclusions:
This case shows that MF with PCM1-JAK2 can be amenable to ruxolitinib. Our findings highlight molecular alterations potentially linked to resistance. Further research is warranted.
