Whole-genome sequencing reveals potent therapeutic strategy for monomorphic epitheliotropic intestinal T-cell lymphoma

Abstract

1. Whole genomic and transcriptomic analyses of MEITL revealed multiple potential therapeutic targets.

2. Synergistic effects of pimozide and romidepsin are shown in a well-characterized MEITL PDX model.

Figure 1.

The whole-genome–wide landscape of MEITL. (A) Oncoplot of recurrent somatic short-variant mutations detected in 4 MEITL tumors. Accompanying compounds that can target the corresponding gene mutations are labeled to the left of the oncoplot. (B) Recurrent somatic copy number alteration across the 4 MEITL using WGS data: copy-gain (left) and copy-loss (right) events. The vertical green line denotes the q = 0.25 (adjusted P value) cutoff for significant copy number events. (C) 17q arm-wide shows that large-scale, copy-neutral, loss-of-heterozygosity alterations were present and affected the STAT5B loci in all our MEITLs. (D) The 100% stacked bar plots comparing the proportions of known COSMIC (Catalogue of Somatic Mutations in Cancer) mutational signatures within each MEITL tumor. The denoted mutational signature numbers are as described at https://cancer.sanger.ac.uk/cosmic/signatures. (E) Circos (http://mkweb.bcgsc.ca/circos) plots depicting the structural rearrangements as links for each WGS sample. Links are colored differently for each type of structural rearrangement: red for duplications, blue for deletions, green for inversions, and black for interchromosomal translocations.

Figure 2.

The synergistic effect of pimozide and romidepsin on a well-characterized MEITL PDX model. (A) Hematoxylin and eosin and immunohistochemical staining of subcutaneous MEITL PDX (P1, P3, and P6) and orthotopic (P3_IP) PDX tumors. (B) Venn diagrams of overlapping single-nucleotide variations (SNV, left) and indels (right) in a primary tumor (red) and a passage 3 subcutaneous tumor (blue). (C) Parabolic response surface maps of pimozide and romidepsin. (D) The combination index of romidepsin with the 20% inhibitory concentration (IC₂₀) of pimozide. ALCL, anaplastic large-cell lymphoma; ATL, acute T-cell leukemia. Data are means ± standard deviation of 3 independent biological replicates. (E) Immunoblots of indicated proteins in MEITL tumor cells treated with control (dimethyl sulfoxide), pimozide, romidepsin, and combination of the 2 drugs for 48 hours at the indicated concentrations. The experiments were repeated at least 3 times. (F) The MIETL PDX tumor growth curves. Treatment with 25 mg/kg pimozide combined with 1 mg/kg romidepsin significantly decreased tumor growth compared with pimozide or romidepsin alone or the vehicle control (n = 3). Error bars indicate standard error of the mean. *P < .05.