The oncoprotein NPM-ALK of anaplastic large-cell lymphoma induces JUNB transcription via ERK1/2 and JunB translation via mTOR signaling

Staber, Philipp B.; Vesely, Paul; Haq, Naznin; Ott, René G.; Funato, Kotaro; Bambach, Isabella; Fuchs, Claudia; Schauer, Silvia; Linkesch, Werner; Hrzenjak, Andelko; Dirks, Wilhelm G.; Sexl, Veronika; Bergler, Helmut; Kadin, Marshall E.; Sternberg, David; Kenner, Lukas; Höefler, Gerald

doi:10.1182/blood-2007-02-071258

Cited by 96 publications

(109 citation statements)

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“…This is in agreement with the results obtained with another constitutively active kinase, nucleophosmin/anaplastic lymphoma kinase (NPM-ALK), which increases JUNB mRNA and JunB protein levels through the activation of ERK and PI3K. 27 Given these results, we next addressed the role of JUNB in the erythropoiesis. With regard to the functions of JUNB in hematopoiesis, it has been shown that this transcription factor plays a key role in the early steps of the myelopoiesis, as JUNB deficiency leads to a transplantable MPD, by expanding the numbers of long-term hematopoietic stem cells and granulocyte/ macrophage progenitors.…”

Section: Discussionsupporting

confidence: 76%

“…19 The activator protein 1 JunB is encoded by an immediate response gene (JUNB gene), whose expression is rapidly stimulated by serum and hematopoietic growth factors [21][22][23][24][25][26] Depending on the cellular background, both positive and negative roles have been described for JUNB in cell proliferation and survival. [27][28][29][30][31][32] In turn, JunB seems to regulate genes involved in cell cycle progression and apoptosis, such as p16, 33 p27, 25 cyclin D1, 34 cyclin A 35 and Bcl-xL. 36 In this study, we observed an overexpression of JUNB mRNA in the bone marrow cells of a JAK2 V617F-positive PV patient, by means of serial analysis of gene expression (SAGE) libraries and studied the role of JUNB in normal and JAK2 V617F-driven erythropoiesis.…”

Section: Introductionmentioning

confidence: 99%

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Constitutive JunB expression, associated with the JAK2 V617F mutation, stimulates proliferation of the erythroid lineage

et al. 2008

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The JAK2 V617F mutation, present in the majority of polycythemia vera (PV) patients, causes constitutive activation of JAK2 and seems to be responsible for the PV phenotype. However, the transcriptional changes triggered by the mutation have not yet been totally characterized. In this study, we performed a large-scale gene expression study using serial analysis of gene expression in bone marrow cells of a newly diagnosed PV patient harboring the JAK2 V617F mutation and in normal bone marrow cells of healthy donors. JUNB was one of the genes upregulated in PV, and we confirmed, by quantitative real-time PCR, an overexpression of JUNB in hematopoietic cells of other JAK2 V617F PV patients. Using Ba/F3-EPOR cell lines and primary human erythroblast cultures, we found that JUNB was transcriptionally induced after erythropoietin addition and that JAK2 V617F constitutively induced JunB protein expression. Furthermore, JUNB knockdown reduced not only the growth of Ba/F3 cells by inducing apoptosis, but also the clonogenic and proliferative potential of human erythroid progenitors. These results establish a role for JunB in normal erythropoiesis and indicate that JunB may play a major role in the development of JAK2 V617F myeloproliferative disorders.

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Section: Discussionsupporting

confidence: 76%

Section: Introductionmentioning

confidence: 99%

Constitutive JunB expression, associated with the JAK2 V617F mutation, stimulates proliferation of the erythroid lineage

et al. 2008

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“…Inhibition of ALK fusion proteins by specific compounds such as crizotinib showed promising clinical responses in ALCL and NSCLC (non-small cell lung cancer) 9,10 . However, ALK mutations conferring resistance to crizotinib have also been reported 11 .Recent studies have linked NPM-ALK expression to induction of AP-1 transcription factors JunB and cJun 12,13 . To investigate their role in NPM-ALK-driven T-cell lymphomas, we conditionally deleted cJun and/or JunB in T-cells of transgenic mice carrying the human NPM-ALK fusion-tyrosine-kinase under the control of the murine CD4-promotor 14 (CD4-NPM-ALK) (Fig.…”

mentioning

confidence: 99%

“…Recent studies have linked NPM-ALK expression to induction of AP-1 transcription factors JunB and cJun 12,13 . To investigate their role in NPM-ALK-driven T-cell lymphomas, we conditionally deleted cJun and/or JunB in T-cells of transgenic mice carrying the human NPM-ALK fusion-tyrosine-kinase under the control of the murine CD4-promotor 14 (CD4-NPM-ALK) (Fig.…”

mentioning

confidence: 99%

PDGFR blockade is a rational and effective therapy for NPM-ALK–driven lymphomas

Laimer

Dolznig

Kollmann

et al. 2012

Nat Med

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121

124

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Anaplastic Large Cell Lymphoma (ALCL) is a Non-Hodgkin lymphoma found in children and young adults with poor survival rates. ALCLs frequently carry a chromosomal translocation that results in expression of the oncoprotein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). The key molecular downstream events required for NPM-ALK triggered lymphoma growth are still not entirely clear. Here we show that the AP-1 proteins cJun and JunB promote lymphoma development and tumor dissemination in a murine NPM-ALK lymphomagenesis model via transcriptional regulation of PDGFRB. Therapeutic inhibition of PDGFRB markedly prolonged survival of NPM-ALK transgenic mice and increased the efficacy of an ALK-specific inhibitor in transplanted NPM-ALK tumors. Remarkably, inhibition of PDGFRs in a late stage patient with refractory NPM-ALK-positive ALCL resulted in complete and sustained remission within 10 days of treatment. Our data identify PDGFRB as novel cJun/JunB target that could be utilized for a highly effective therapy to cure ALCL. 3ALCLs are T-cell lymphomas 1,2 that comprise 10-20% of all Non-Hodgkin's lymphoma cases in children and 3% in adults 3 . About half of ALCL cases are positive for NPM-ALK fusion proteins caused by t(2;5)(p23;q35) translocation 4 . ALK translocations or point mutations have also been described in DLBCLs (diffuse large B-cell lymphomas) and in several nonlymphoid neoplasms [5][6][7][8] . Inhibition of ALK fusion proteins by specific compounds such as crizotinib showed promising clinical responses in ALCL and NSCLC (non-small cell lung cancer) 9,10 . However, ALK mutations conferring resistance to crizotinib have also been reported 11 .Recent studies have linked NPM-ALK expression to induction of AP-1 transcription factors JunB and cJun 12,13 . To investigate their role in NPM-ALK-driven T-cell lymphomas, we conditionally deleted cJun and/or JunB in T-cells of transgenic mice carrying the human NPM-ALK fusion-tyrosine-kinase under the control of the murine CD4-promotor 14 (CD4-NPM-ALK) (Fig. 1a). Gene deletion was confirmed by DNA genotyping (data not shown), real-time PCR, Western blotting and immunohistochemistry (IHC) (Suppl. (Fig.1b), however, inactivation of both, cJun and JunB, in CD4-NPM-ALK-CD4 ΔΔJun mice resulted in significantly prolonged survival (Fig. 1b). CD4-NPM-ALK-CD4 ΔΔJun lymphomas showed markedly reduced proliferation and significantly increased apoptosis when compared to CD4-NPM-ALK lymphomas ( Fig. 1c; Suppl. Fig. S2a,b). Consistently, (Fig. 2d) suggesting a transcriptional regulation of PDGFRB by Jun proteins. Consistently, AP-1 consensus sequences were identified within the murine PDGFRB promoter and first intron that were conserved among other species (Suppl. Fig. S3b,c) 15,16 . Moreover, analysis of ENCODE transcription factor binding tracks revealed binding of cJun and JunB to the PDGFRB intronic AP-1 site in the human K562 leukemia cell line (Suppl. Fig. S3d) 15,17 . CD4-NPM-ALK-CD4EMSA analysis of nuclear extracts from NPM-ALK lymphomas demonstrated AP-1 DNA ...

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“…ALK + ALCL bears the t(2;5) (p23;q35) translocation in greater than 80% of cases, which results in the expression of the chimeric nucleophosmin (NPM)-ALK (1)(2)(3)(4). The consequence of the fusion is constitutive ALK expression, which leads to the activation of many different growth-promoting and antiapoptotic pathways, including PI3K/Akt1/mTOR (5)(6)(7)(8), Jak/Stat (9-11), cJun, JunB (12)(13)(14), and c-myc (12,15). The transforming capacity of the NPM-ALK fusion was shown for the first time in murine chimeras in which lethally irradiated recipients were rescued with NPM-ALK-transduced bone marrow (4,16,17) as well as in several transgenic mouse models that expressed the NPM-ALK fusion protein in hematopoietic cells (14,18,19).…”

mentioning

confidence: 99%

Identification of differential and functionally active miRNAs in both anaplastic lymphoma kinase (ALK)⁺and ALK⁻anaplastic large-cell lymphoma

Merkel

Hamacher

Laimer

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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133

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Aberrant anaplastic lymphoma kinase (ALK) expression is a defining feature of many human cancers and was identified first in anaplastic large-cell lymphoma (ALCL), an aggressive non-Hodgkin T-cell lymphoma. Since that time, many studies have set out to identify the mechanisms used by aberrant ALK toward tumorigenesis. We have identified a distinct profile of micro-RNAs (miRNAs) that characterize ALCL; furthermore, this profile distinguishes ALK + from ALK − subtypes, and thus points toward potential mechanisms of tumorigenesis induced by aberrant ALK. Using a nucleophosmin-ALK transgenic mouse model as well as human primary ALCL tumor tissues and human ALCL-derived cell lines, we reveal a set of overlapping deregulated miRNAs that might be implicated in the development and progression of ALCL. Importantly, ALK + and ALK − ALCL could be distinguished by a distinct profile of "oncomirs": Five members of the miR-17-92 cluster were expressed more highly in ALK + ALCL, whereas miR-155 was expressed more than 10-fold higher in ALK − ALCL. Moreover, miR-101 was down-regulated in all ALCL model systems, but its forced expression attenuated cell proliferation only in ALK + and not in ALK − cell lines, perhaps suggesting different modes of ALK-dependent regulation of its target proteins. Furthermore, inhibition of mTOR, which is targeted by miR-101, led to reduced tumor growth in engrafted ALCL mouse models. In addition to future therapeutical and diagnostic applications, it will be of interest to study the physiological implications and prognostic value of the identified miRNA profiles.micro-RNA | mTOR | miR-155 | miR-101

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The oncoprotein NPM-ALK of anaplastic large-cell lymphoma induces JUNB transcription via ERK1/2 and JunB translation via mTOR signaling

Cited by 96 publications

References 48 publications

Constitutive JunB expression, associated with the JAK2 V617F mutation, stimulates proliferation of the erythroid lineage

Constitutive JunB expression, associated with the JAK2 V617F mutation, stimulates proliferation of the erythroid lineage

PDGFR blockade is a rational and effective therapy for NPM-ALK–driven lymphomas

Identification of differential and functionally active miRNAs in both anaplastic lymphoma kinase (ALK)⁺and ALK⁻anaplastic large-cell lymphoma

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The oncoprotein NPM-ALK of anaplastic large-cell lymphoma induces JUNB transcription via ERK1/2 and JunB translation via mTOR signaling

Cited by 96 publications

References 48 publications

Constitutive JunB expression, associated with the JAK2 V617F mutation, stimulates proliferation of the erythroid lineage

Constitutive JunB expression, associated with the JAK2 V617F mutation, stimulates proliferation of the erythroid lineage

PDGFR blockade is a rational and effective therapy for NPM-ALK–driven lymphomas

Identification of differential and functionally active miRNAs in both anaplastic lymphoma kinase (ALK)+and ALK−anaplastic large-cell lymphoma

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Identification of differential and functionally active miRNAs in both anaplastic lymphoma kinase (ALK)⁺and ALK⁻anaplastic large-cell lymphoma