Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma with novel FGFR1 fusion treated with pemigatinib

doi:10.1182/bloodadvances.2024014928

. 2025 Apr 22;9(8):1786-1790.

doi: 10.1182/bloodadvances.2024014928.

Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma with novel FGFR1 fusion treated with pemigatinib

Carlos A Torres-Cabala^{1

2

3}, Julia Arreola Yescas⁴, Yue Zhang⁴, Auris Huen², Gaur Sumit⁵, Kristy Tefft⁴, Guilin Tang⁶, Jonathan L Curry^{1

2

3}, Jillian Gunther⁷, Bouthaina Dabaja⁷, Swaminathan Iyer⁸, Roberto N Miranda⁶, Jaehyuk Choi⁴, Valentina Nardi⁹

Affiliations

¹ Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX.
² Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX.
³ Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX.
⁴ Department of Dermatology, Northwestern University, Chicago, IL.
⁵ Division of Hematology/Oncology, Texas Tech University Health Sciences Center, Lubbock, TX.
⁶ Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX.
⁷ Department of Radiation Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX.
⁸ Department of Lymphoma/Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.
⁹ Department of Pathology, Harvard Medical School, Boston, MA.

PMID: 39825823
PMCID: PMC12008514
DOI: 10.1182/bloodadvances.2024014928

Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma with novel FGFR1 fusion treated with pemigatinib

Carlos A Torres-Cabala et al. Blood Adv. 2025.

. 2025 Apr 22;9(8):1786-1790.

doi: 10.1182/bloodadvances.2024014928.

Authors

Affiliations

¹ Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX.
² Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX.
³ Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX.
⁴ Department of Dermatology, Northwestern University, Chicago, IL.
⁵ Division of Hematology/Oncology, Texas Tech University Health Sciences Center, Lubbock, TX.
⁶ Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX.
⁷ Department of Radiation Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX.
⁸ Department of Lymphoma/Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.
⁹ Department of Pathology, Harvard Medical School, Boston, MA.

PMID: 39825823
PMCID: PMC12008514
DOI: 10.1182/bloodadvances.2024014928

No abstract available

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Conflict of interest statement

Conflict-of-interest disclosure: J.C. is a cofounder and stakeholder in Moonlight Bio, which has no relevance to the findings in this manuscript. The remaining authors declare no competing financial interests.

Figures

**Figure 1.**
**Clinical and histopathological appearance of primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphoma with *SATB1*::*FGFR1* fusion.** (A) Clinical presentation of rapidly progressing ulcerated lesions on upper extremities and chest. (B) Ulcerated lesions on the left foot showing clinical remission after 4 weeks of therapy with pemigatinib. (C) Skin biopsy. Histological section shows a markedly epidermotropic and adnexotropic lymphoma (original magnification ×40; hematoxylin and eosin [H&E]). (D) The epidermotropic lymphocytes show cytologic atypia and hyperchromasia (original magnification ×200; H&E). (E) The atypical lymphocytes are positive for CD3 (original magnification ×100; immunohistochemistry). (F) The lymphoma cells express CD8 (original magnification ×100; immunohistochemistry). (G) The lymphoma cells express TCR βF1, indicating that the phenotype of the lymphoma cells is α/β (original magnification ×200; immunohistochemistry). (H) The atypical epidermotropic cells are positive for TIA-1, supporting a cytotoxic phenotype of this lymphoma (original magnification ×400; immunohistochemistry).

**Figure 2.**
*SATB1*::*FGFR1* rearrangement demonstrated by next-generation sequencing and fluorescence in situ hybridization (FISH).SATB1::*FGFR1* can be inhibited by pemigatinib in vitro but *FGFR1* V561L mutation drives drug resistance. (A) *SATB1*::*FGFR1* fusion transcript detected by anchored multiplex polymerase chain reaction. An in-frame fusion involving *SATB1* (exon 7) and *FGFR1* (exon 10) results in juxtaposition of amino acid 402 of SATB1 and amino acid 429 of FGFR1. Of note, the FGFR1 TK domain starts at amino acid 478. (B) FISH analysis using *FGFR1* break apart probe, 5′*FGFR1* (centromeric [green])/3′*FGFR1* (telomeric [red]), showed 1 red 1 fusion signal pattern, indicating 5′*FGFR1* deletion and unbalanced *FGFR1* rearrangement. (C) Cell viability assays. *SATB1:FGFR1* cDNA (Twist Bioscience) was mutagenized by Gibson cloning, subcloned into pCDH-CMV-MCS-EF1-copGFP vector (Systems Biosciences), and chemically transfected by FuGENE (Promega Corp) into 293-LentiX viral packaging cells. Retroviruses encoding empty vector control, wild-type FGFR1, and SATB1-FGFR1 were transduced into Ba/F3 cells. Successfully transduced Ba/F3 cells were seeded at a cell density of 1 × 10⁶/mL in a 96-well plate in the presence or absence of interleukin-3 (IL-3; 10 ng/mL; PepoTech). Transduced Ba/F3 cells were cell sorted based on green fluorescent protein positivity. On day 0, cells were seeded without IL-3 at 10⁶ cells per mL. Results show cell counts and represent the mean ± standard deviation (SD) of triplicates. Statistical differences were tested using multiple comparison 2-way analysis of variance (ANOVA); ∗∗∗P < .0001. (D) Cell viability assay to determine 50% inhibitory concentration (IC₅₀) values of pemigatinib in SATB1-FGFR1–expressing Ba/F3 cells without IL-3. A total of 10⁶ cell per mL were cultured with pemigatinib (INCB054828, Selleckchem) or vehicle control in a 96-well plate. CellTiter-Glo luminescent reagent (Promega) was added after 48 hours (BioTek Cytation 5). IC₅₀ values were determined using a nonlinear regression model in GraphPad Prism version 10 (GraphPad Software). Results show cell counts and represent the means ± SD of triplicates. (E) Western blots of SATB1-FGFR1–expressing Ba/F3 cells. Cells were transduced with SATB1-FGFR1 and treated with pemigatinib for indicated concentrations for 48 hours. Antibodies against pSTAT5 (4322), pFGFR1 (52928), and β-actin (4970) were obtained from Cell Signaling Technology. (F) Fusion protein with domains of SATB1 and FGFR1. The NLS, ULD, the CUTL DNA binding domain, and a truncated CUT domain are preserved in SATB1. The kinase domain of FGFR1 is retained. Point mutations are given in fusion protein coordinates and original FGFR1 coordinates in parentheses. WGS was performed by Admera (South Plainfield, NJ) using the Kapa Hyper Prep (Roche) kit. RNA sequencing was performed by Admera (South Plainfield, NJ) using the KAPA RNA HyperPrep kit with RiboErase (HMR) (Roche) kit. Raw paired-end Fastq reads from whole-exome sequencing were aligned to GRCh38.p13 and standardized using GATK 4.4.0.0 best practices. Additionally, mutations in *FGFR1* were manually verified with Integrative Genomics Viewer. Raw paired-end RNA-sequencing Fastq reads were aligned to GRCh38.p13 with GENCODE version 30 transcripts using STAR version 2.7.10. Splice junctions were separated and realigned to the genome using GATK4.4.0.0. HaplotypeCaller was used to identify single-nucleotide changes compared with reference genome. STAR-fusion was performed on raw Fastq reads to identify expressed fusion transcripts. (G) Cell viability assay to determine IC₅₀ values of pemigatinib in Ba/F3 cells expressing SATB1-FGFR1 variants. Cells were cultured as in panel D and harvested after 48 hours. Results show cell counts and represent the means ± SD of triplicates. Statistical differences were tested using multiple comparisons 2-way ANOVA; ∗∗∗∗P < .0001. CUTL, CUT1-like; DMSO, dimethyl sulfoxide; Log, base 10 logarithm; NLS, nuclear localization signal; NR, not reached; ns, not significant; ULD, ubiquitin-like domain.

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[1] Zheng Z, Liebers M, Zhelyazkova B, et al. Anchored multiplex PCR for targeted next-generation sequencing. Nat Med. 2014;20(12):1479–1484. - PubMed

[2] Zheng Z, Liebers M, Zhelyazkova B, et al. Anchored multiplex PCR for targeted next-generation sequencing. Nat Med. 2014;20(12):1479–1484. - PubMed

[3] Robinson JT, Thorvaldsdottir H, Winckler W, et al. Integrative genomics viewer. Nat Biotechnol. 2011;29(1):24–26. - PMC - PubMed

[4] Robinson JT, Thorvaldsdottir H, Winckler W, et al. Integrative genomics viewer. Nat Biotechnol. 2011;29(1):24–26. - PMC - PubMed

[5] Dobin A, Davis CA, Schlesinger F, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29(1):15–21. - PMC - PubMed

[6] Dobin A, Davis CA, Schlesinger F, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29(1):15–21. - PMC - PubMed

[7] DePristo MA, Banks E, Poplin R, et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet. 2011;43(5):491–498. - PMC - PubMed

[8] DePristo MA, Banks E, Poplin R, et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet. 2011;43(5):491–498. - PMC - PubMed

[9] Cibulskis K, Lawrence MS, Carter SL, et al. Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat Biotechnol. 2013;31(3):213–219. - PMC - PubMed

[10] Cibulskis K, Lawrence MS, Carter SL, et al. Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat Biotechnol. 2013;31(3):213–219. - PMC - PubMed

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Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma with novel FGFR1 fusion treated with pemigatinib

Affiliations

Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma with novel FGFR1 fusion treated with pemigatinib

Authors

Affiliations

Conflict of interest statement

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