Aurora Kinase A Is Upregulated in Cutaneous T-Cell Lymphoma and Represents a Potential Therapeutic Target

Humme, Daniel; Haider, Ahmed; Möbs, Markus; Mitsui, Hiroshi; Suárez‐Fariñas, Mayte; Ohmatsu, Hanako; Geilen, Cyprienne Isabell; Eberle, Jürgen; Krueger, James G.; Beyer, Marc; Hummel, Michael; Anagnostopoulos, Ioannis; Sterry, Wolfram; Assaf, Chalid

doi:10.1038/jid.2015.139

Cited by 24 publications

(31 citation statements)

References 37 publications

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“…44 We also showed that sorted CD8 1 T cells have engraftment properties (Figure 4D-E; data not shown) and that recipients transplanted with Ts1Rhr-Jak3 A572V donor cells mostly develop CD8 1 T-cell expansion, indicating that increased dosage of trisomic genes located in the DSCR functionally cooperate with mutant JAK3 to maintain this phenotype. Because gain of chromosome 21 is found in 7% to 10% of human CTCLs, 16,43 we reanalyzed the transcription profiles of human CTCL samples 45 and observed that both ETS1 and FLI1 (2 Ets-related transcription factors homologous to Ets2 and Erg contained in the DSCR 34 ) were overexpressed 3.17-fold and 3.57-fold, respectively (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Partial trisomy 21 contributes to T-cell malignancies induced by JAK3-activating mutations in murine models

et al. 2018

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JAK3-activating mutations are commonly seen in chronic or acute hematologic malignancies affecting the myeloid, megakaryocytic, lymphoid, and natural killer (NK) cell compartment. Overexpression models of mutant JAK3 or pharmacologic inhibition of its kinase activity have highlighted the role that these constitutively activated mutants play in the T-cell, NK cell, and megakaryocytic lineages, but to date, the functional impact of JAK3 mutations at an endogenous level remains unknown. Here, we report a JAK3 knockin mouse model and demonstrate that activated JAK3 leads to a progressive and dose-dependent expansion of CD8 T cells in the periphery before colonization of the bone marrow. This phenotype is dependent on the γc chain of cytokine receptors and presents several features of the human leukemic form of cutaneous T-cell lymphoma (L-CTCL), including skin involvements. We also showed that the JAK3-positive malignant cells are transplantable and phenotypically heterogeneous in bone marrow transplantation assays. Interestingly, we revealed that activated JAK3 functionally cooperates with partial trisomy 21 in vivo to enhance the L-CTCL phenotype, ultimately leading to a lethal and fully penetrant disorder. Finally, we assessed the efficacy of JAK3 inhibition and showed that CTCL JAK3-positive T cells are sensitive to tofacitinib, which provides additional preclinical insights into the use of JAK3 inhibitors in these disorders. Altogether, this JAK3 knockin model is a relevant new tool for testing the efficacy of JAK inhibitors in JAK3-related hematopoietic malignancies.

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Section: Discussionmentioning

confidence: 99%

Partial trisomy 21 contributes to T-cell malignancies induced by JAK3-activating mutations in murine models

et al. 2018

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“…Overexpression of Aurora kinase A (AURKA) is associated with tumorigenesis [84]. Wakahara et al have reported that EWS-FLI1 upregulates the levels of Aurora kinase A and B by directly binding to their promoter regions [85].…”

Section: Targeted Therapymentioning

confidence: 99%

Potential approaches to the treatment of Ewing's sarcoma

Guo

et al. 2016

Oncotarget

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Ewing’s sarcoma (ES) is a highly aggressive and metastatic tumor in children and young adults caused by a chromosomal fusion between the Ewing sarcoma breakpoint region 1 (EWSR1) gene and the transcription factor FLI1 gene. ES is managed with standard treatments, including chemotherapy, surgery and radiation. Although the 5-year survival rate for primary ES has improved, the survival rate for ES patients with metastases or recurrence remains low. Several novel molecular targets in ES have recently been identified and investigated in preclinical and clinical settings, and targeting the function of receptor tyrosine kinases (RTKs), the fusion protein EWS-FLI1 and mTOR has shown promise. There has also been increasing interest in the immune responses of ES patients. Immunotherapies using T cells, NK cells, cancer vaccines and monoclonal antibodies have been considered for ES, especially for recurrent patients. Because understanding the pathogenesis of ES is extremely important for the development of novel treatments, this review focuses on the mechanisms and functions of targeted therapies and immunotherapies in ES. It is anticipated that integrating the knowledge obtained from basic research and translational and clinical studies will lead to the development of novel therapeutic strategies for the treatment of ES.

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“…Thus as foretold, IL-2 and IL-15 appear to operate in the same pathway in MAC-1 cells. The analysis of CTCL patient biopsies [28] further showed upregulation of genes that are subject to IL-2 mediated upregulation in MAC-1 cells and associated with aggressive phase (MAC-2A) expression profiles, revealing overall upregulation of IL15, JAK3, SOCS1 and TNFRSF9 or CCL17, IFN-gamma, IL17A/F, IL21, IL22, IL6 and IL9 in some patients (Supplementary Figure 3). In contrast to IL-2, IL-15 is produced in the skin and may therefore be more pathologically relevant [29].…”

Section: Resultsmentioning

confidence: 99%

Th17 cytokine differentiation and loss of plasticity after SOCS1 inactivation in a cutaneous T-cell lymphoma

et al. 2016

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We propose that deregulated T-helper-cell (Th) signaling underlies evolving Th17 cytokine expression seen during progression of cutaneous T-cell lymphoma (CTCL). Accordingly, we developed a lymphoma progression model comprising cell lines established at indolent (MAC-1) and aggressive (MAC-2A) CTCL stages. We discovered activating JAK3 (V722I) mutations present at indolent disease, reinforced in aggressive disease by novel compound heterozygous SOCS1 (G78R/D105N) JAK-binding domain inactivating mutations. Though isogenic, indolent and aggressive-stage cell lines had diverged phenotypically, the latter expressing multiple Th17 related cytokines, the former a narrower profile. Importantly, indolent stage cells remained poised for Th17 cytokine expression, readily inducible by treatment with IL-2 - a cytokine which mitigates Th17 differentiation in mice. In indolent stage cells JAK3 expression was boosted by IL-2 treatment. Th17 conversion of MAC-1 cells by IL-2 was blocked by pharmacological inhibition of JAK3 or STAT5, implicating IL2RG - JAK3 – STAT5 signaling in plasticity responses. Like IL-2 treatment, SOCS1 knockdown drove indolent stage cells to mimic key aggressive stage properties, notably IL17F upregulation. Co-immunoprecipitation experiments showed that SOCS1 mutations abolished JAK3 binding, revealing a key role for SOCS1 in regulating JAK3/STAT5 signaling. Collectively, our results show how JAK/STAT pathway mutations contribute to disease progression in CTCL cells by potentiating inflammatory cytokine signaling, widening the potential therapeutic target range for this intractable entity. MAC-1/2A cells also provide a candidate human Th17 laboratory model for identifying potentally actionable CTCL markers or targets and testing their druggability in vitro.

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Aurora Kinase A Is Upregulated in Cutaneous T-Cell Lymphoma and Represents a Potential Therapeutic Target

Cited by 24 publications

References 37 publications

Partial trisomy 21 contributes to T-cell malignancies induced by JAK3-activating mutations in murine models

Partial trisomy 21 contributes to T-cell malignancies induced by JAK3-activating mutations in murine models

Potential approaches to the treatment of Ewing's sarcoma

Th17 cytokine differentiation and loss of plasticity after SOCS1 inactivation in a cutaneous T-cell lymphoma

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