Amplification and overexpression of JUNB is associated with primary cutaneous T-cell lymphomas

Mao, Xin; Orchard, Guy; Lillington, Debra M.; Russell‐Jones, Robin; Young, Bryan D.; Whittaker, Sean

doi:10.1182/blood-2002-08-2434

Cited by 179 publications

(151 citation statements)

References 41 publications

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“…Moreover, a subset of cutaneous T-cell lymphomas including cutaneous anaplastic large cell lymphoma tumors also express JunB. 6 It is tempting to speculate that JunB, in CD30 þ non-Hodgkin lymphomas and lymphomatoid papulosis, induces CD30 expression through interacting with the CD30 gene promoter, as has been shown in Hodgkin and Reed-Sternberg cells of Hodgkin lymphoma. 5 The underlying mechanism(s) of JunB overexpression in CD30 þ lymphomas and lymphomatoid papulosis are largely unknown.…”

Section: Discussionmentioning

confidence: 96%

“…5 Among nonHodgkin lymphomas, a subset of cases of cutaneous lymphoma including cutaneous anaplastic large cell lymphoma were reported to overexpress JunB. 6 In this study, we surveyed JunB expression in a variety of CD30 þ lymphoma types and in lymphomatoid papulosis. We have shown that JunB overexpression is a common finding in virtually all CD30 þ lymphomas.…”

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confidence: 99%

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JunB expression is a common feature of CD30+ lymphomas and lymphomatoid papulosis

et al. 2005

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JunB is a member of the Jun family of proteins that are components of the AP-1 transcription factor complex. AP-1 is involved in cell proliferation and apoptosis. Recent evidence suggests that Hodgkin and ReedSternberg cells overexpress JunB and that JunB facilitates constitutive CD30 expression by binding to an AP-1 site in the CD30 promoter. In this study we surveyed JunB expression in a variety of CD30 þ lymphoma types including 42 cases of anaplastic large cell lymphoma, 36 classical Hodgkin lymphoma, 15 cutaneous anaplastic large cell lymphoma, and 11 CD30 þ diffuse large B-cell lymphoma. In addition, seven cases of nodular lymphocyte-predominant Hodgkin lymphoma and 42 diffuse large B-cell lymphoma, known to be CD30À, were analyzed. JunB expression was assessed using tissue microarrays, immunohistochemistry and a monoclonal antibody specific for JunB. Expression of JunB was observed in 41 of 42 cases of anaplastic large cell lymphoma, including all 21 cases positive for anaplastic lymphoma kinase and 20 of 21 (95%) negative for anaplastic lymphoma kinase. JunB was also expressed in all cases of classical Hodgkin lymphoma, cutaneous anaplastic large cell lymphoma and CD30 þ diffuse large B-cell lymphoma, and in lymphomatoid papulosis. By contrast, all nodular lymphocyte-predominant Hodgkin lymphomas and diffuse large B-cell lymphomas that were CD30À were also JunBÀ. We conclude that JunB is expressed in virtually all CD30 þ lymphomas and is a potential target for experimental therapy in patients with these tumors.

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Section: Discussionmentioning

confidence: 96%

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confidence: 99%

JunB expression is a common feature of CD30+ lymphomas and lymphomatoid papulosis

et al. 2005

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“…JunB is expressed at high levels in Hodgkin's lymphoma and T-cell malignancies (Mao et al, 2003;Rassidakis et al, 2005). In contrast, it is not detectable in most human B-lymphoid malignancies and silenced in advanced stages of myeloid leukemia (Yang et al, 2003;Szremska et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, JunB is altered in human lymphoid malignancies. JunB is overexpressed in Hodgkin's lymphoma and in T-cell tumors, but only expressed at low levels or entirely missing in B-lymphoid malignancies (Mao et al, 2003;Szremska et al, 2003;Rassidakis et al, 2005). This observation is remarkable, as AP-1 family members are generally expressed at high levels in transformed cells (Wu et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

JunB is a gatekeeper for B-lymphoid leukemia

et al. 2007

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Loss of JunB has been observed in human leukemia and lymphoma, but it remains unknown, whether this loss is relevant to disease progression. Here, we investigated the consequences of JunB deficiency using Abelson-induced B-lymphoid leukemia as a model system. Mice deficient in JunB expression succumbed to Abelson-induced leukemia with increased incidence and significantly reduced latency. Similarly, bcr/abl p185-transformed JunB-deficient (junB D/D ) cells induced leukemia in RAG2 À/À mice displaying a more malignant phenotype. These observations indicated that cell intrinsic effects within the junB D/D tumor cells accounted for the accelerated leukemia development. Indeed, explantated bcr/abl p185 transformed junB D/D cells proliferated faster than the control cells. The proliferative advantage emerged slowly after the initial transformation process and was associated with increased expression levels of the cell cycle kinase cdk6 and with decreased levels of the cell cycle inhibitor p16 INK4a . These alterations were due to irreversible reprogramming of the cell, because -once established -accelerated disease induced by junB D/D cells was not reverted by re-introducing JunB. Consistent with this observation, we found that the p16 promoter was methylated. Thus, JunB functions as a gatekeeper during tumor evolution. In its absence, transformed leukemic cells acquire an enhanced proliferative capacity, which presages a more malignant disease.

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“…The level and the activity of PAK1 are increased in myelodysplastic syndrome (MDS) (Pandolfi et al , 2015), and a gain in PAK1 gene copy number was found in cutaneous T cell lymphoma (mycosis fungoides/Sezary syndrome) (Mao et al , 2003). The level of PAK2 is increased in mantle cell lymphoma (MCL) and in activated B‐cell like diffuse large B cell lymphoma (ABC‐like DLBCL) that harbour 3q29 amplifications.…”

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confidence: 99%

Expansion of BCR/ABL1⁺ cells requires PAK2 but not PAK1

et al. 2017

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SummaryThe p21‐activated kinases (PAKs) are key nodes in oncogenic signalling pathways controlling growth, survival, and motility of cancer cells. Their activity is increased in many human cancers and is associated with poor prognosis. To date, PAK deregulation has mainly been studied in solid tumours, where PAK1 and PAK4 are the main isoforms deregulated. We show that PAK1 and PAK2 are the critical isoforms in a BCR/ABL1 + haematopoietic malignancy. In suspension, leukaemic cells deficient for PAK1 and PAK2 undergo apoptosis, while the loss of either protein is well tolerated. Transfer of medium conditioned by shPAK2‐ but not shPAK1‐expressing leukaemic cells interferes with endothelial cell growth. We found that leukaemic cells produce exosomes containing PAK2. Transfer of isolated exosomes supports endothelial cell proliferation. In parallel, we found that leukaemic cells explicitly require PAK2 to grow towards an extracellular matrix. PAK2‐deficient cells fail to form colonies in methylcellulose and to induce lymphomas in vivo. PAK2 might therefore be the critical isoform in leukaemic cells by controlling tumour growth in a dual manner: vascularization via exosome‐mediated transfer to endothelial cells and remodelling of the extracellular matrix. This finding suggests that the PAK2 isoform represents a promising target for the treatment of haematological diseases.

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Amplification and overexpression of JUNB is associated with primary cutaneous T-cell lymphomas

Cited by 179 publications

References 41 publications

JunB expression is a common feature of CD30+ lymphomas and lymphomatoid papulosis

JunB expression is a common feature of CD30+ lymphomas and lymphomatoid papulosis

JunB is a gatekeeper for B-lymphoid leukemia

Expansion of BCR/ABL1⁺ cells requires PAK2 but not PAK1

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Amplification and overexpression of JUNB is associated with primary cutaneous T-cell lymphomas

Cited by 179 publications

References 41 publications

JunB expression is a common feature of CD30+ lymphomas and lymphomatoid papulosis

JunB expression is a common feature of CD30+ lymphomas and lymphomatoid papulosis

JunB is a gatekeeper for B-lymphoid leukemia

Expansion of BCR/ABL1+ cells requires PAK2 but not PAK1

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Product

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Expansion of BCR/ABL1⁺ cells requires PAK2 but not PAK1