Primary cutaneous gamma/delta T-cell lymphoma with simultaneous JAK2 and TP63 rearrangements: a new double-hit?

Graphical Abstract

Correspondence

Recurrent chromosomal rearrangements are a hallmark of many lymphomas and other cancers. They fall into two main categories: those that cause oncogene overexpression via juxtaposition with an active enhancer or other regulatory region of DNA, and those that generate novel fusion genes. Among B-cell lymphomas, tumors with more than one oncogenic chromosomal rearrangement, known as double-hit lymphomas, have emerged as a particularly aggressive group of tumors. The occurrence of this phenomenon in T-cell lymphomas is poorly understood. Here, we report the first known case of a T-cell lymphoma with simultaneous JAK2 and TP63 fusions. The patient had an aggressive clinical course refractory to a JAK inhibitor and multiple other therapies. This case underscores the complexity of T-cell lymphoma genomics and the challenges for devising effective targeted therapies.

A 78 year-old male presented with a 3 cm ulcerating lesion on the scalp/forehead (Figure 1A), which had developed rapidly over several weeks. PET and bone marrow biopsy were negative. The lesion was unresponsive to intralesional steroids. A biopsy was performed at another institution; a recurrent forearm lesion (Figure 1A, inset) biopsied at our institution showed similar features. There was an extensive atypical lymphoid infiltrate involving the full thickness of the dermis, focally extending into the subcutaneous fat (Figure 1B). The atypical cells were medium-sized to occasionally large with visible nucleoli (Figure 1C). There was marked epidermotropism (Figure 1D). By immunohistochemistry (Figure 2A–C), the cells were positive for CD3, granzyme B, p63, TIA1, and TCR-δ. They were negative for CD1a, CD2, CD4, CD5, CD7, CD8, CD20, CD30, CD56, TCR-β (beta-F1), and TdT. EBV was negative by EBER in situ hybridization. The patient was diagnosed with primary cutaneous gamma/delta T-cell lymphoma (PCGDTCL).

Figure 1. Clinical and histological features.

(A) The presenting site, a large, ulcerating lesion on the scalp, is shown. The inset shows a nodular lesion on the forearm, which was the site biopsied at our institution. (B) At low power, the tumor is seen to infiltrate the full thickness of the dermis and focally extend to the subcutaneous fat (H&E, 20×). (C) At high power, the tumor cells are mostly medium-sized to occasionally large and have visible nucleoli (H&E, 1000×). (D) The tumor cells show extensive epidermotropism (H&E, 400×).

Figure 2. Immunophenotypic and genetic features.

(A) The tumor cells are positive for CD3 (400×). (B) The tumor cells are positive for T-cell receptor-δ and negative for T-cell receptor-β (beta-F1; inset; both, 400×). (C) The tumor cells show strong, uniform nuclear staining for p63 (400×). Other immunophenotypic markers are described in the text. (D) Breakapart FISH for the JAK2 locus (9p24) shows separation of the 3’ red signals and 5’ green signals (1000×), indicating the presence of a rearrangement. (E) Breakapart FISH for the TP63 locus (3q28) shows separation of the 5’ red signals and 3’ green signals (1000×), indicating the presence of a rearrangement. (F) Dual-color, dual-fusion FISH for the TP63 locus (3q28; red) and the TBL1XR1 locus (3q26.32; green) shows two yellow fusion signals (1000×), consistent with the classic 3q inversion, inv(3)(q26q28).

The patient was treated with cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) with initial improvement but regrowth by the end of 4 cycles. Radiation provided transient disease control but new lesions developed at multiple sites. Tempus (Chicago) xT 648-gene DNA and whole-transcriptome RNA next-generation sequencing was performed to identify candidate therapeutic targets. This revealed PCM1::JAK2 and TBL1XR1::TP63 fusions; mutations of CDKN2A, TERT, and GRIN2A; and copy number loss of ING1. Fluorescence in situ hybridization (FISH) using breakapart probes confirmed rearrangements of JAK2 (Figure 2D) and TP63 (Figure 2E). Dual-color, dual-fusion FISH showed TBL1XR1::TP63 fusion (Figure 2F). Both rearrangements were present in >70% of total nuclei, suggesting co-occurrence in the same tumor cell population. The patient was treated with the JAK1/2 inhibitor ruxolitinib; however, his disease progressed and did not respond to either bendamustine or the histone deacetylase inhibitor romidepsin. PET showed involvement of the rectum, soft tissue, nasal passage, eyelid, and Waldeyer’s ring. He was transitioned into palliative care treatment and died 15 months after diagnosis.

To our knowledge, this is the first case of human cancer with concurrent JAK2 and TP63 rearrangements. PCGDTCL is a generally aggressive malignancy of the innate immune system. Genetic studies have shown oncogenic mutations in the JAK-STAT pathway, particularly of STAT3, STAT5B, JAK3, and SOCS1, as well as in the MAPK, MYC, and chromatin modification pathways.¹ Recurrent fusions have not been described.

JAK2 fusions with PCM1 and other partners are recurrent in myeloid malignancies, B-lymphoblastic leukemia/lymphoma, and mature T-cell neoplasms. These fusions juxtapose the N-terminal dimerization domain of the partner gene and the C-terminal JAK2 kinase domain, leading to constitutive activation of the JAK2 protein tyrosine kinase. Among T-cell neoplasms, JAK2 fusions have been reported in T-cell lymphoproliferative disorders of the gastrointestinal tract, ALK-negative anaplastic large cell lymphoma (ALCL) and other CD30-positive T-cell lymphomas, primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma, and mycosis fungoides (MF).² TP63 rearrangements, most commonly with TBL1XR1 but also with other partners, are associated with aggressive clinical behavior in systemic and occasionally cutaneous ALK-negative ALCLs, and also have been reported in peripheral T-cell lymphomas, transformed MF, B-cell lymphomas, and rare carcinomas. TP63 encodes p63, a member of the p53 family of transcription factors; oncogenic fusions occur when an N-truncated form of TP63 lacking the transactivation domain is joined to the 5’ portion of the partner gene.³

The present case, carrying oncogenic fusions of both JAK2 and TP63, was clinically aggressive and refractory to multiple therapies, including the JAK1/2 inhibitor ruxolitinib. Studies in cell lines and mice have shown that PCM1::JAK2 activates STAT5 and can be specifically targeted by JAK inhibitors.⁴ Ruxolitinib has shown efficacy against T-cell lymphomas in clinical trials⁵ and has induced remissions in patients with PCM1::JAK2-associated leukemias.⁶ Effective strategies to target TP63 fusions have not been established, but recent data suggest possible sensitivity to EZH2 inhibition.⁷ The presence of the TP63 fusion likely contributed to the aggressive disease course in this patient, including resistance to a JAK inhibitor. Loss-of-function alterations in CDKN2A and gain-of-function mutations in TERT may also contribute the pathogenesis of PCGDTCL.¹ Loss-of-function alterations in GRNA2A and ING1 have been associated with cancer progression in general, but their role in PCGDTCL is unknown.

Aggressive double-hit B-cell lymphomas, most commonly with concurrent rearrangements of MYC and BCL2, have been extensively studied, but little is known about dual rearrangements in T-cell lymphomas. The clinical course of the present case highlights how the presence of multiple oncogenic hits represents a challenge to targeted therapy approaches.

Data Availability Statement:

There are no datasets associated with this manuscript.