Centrosomal targeting of tyrosine kinase activity does not enhance oncogenicity in chronic myeloproliferative disorders

Bochtler, Tilmann; Kirsch, Michael; Maier, Bettina; Bachmann, Julie; Klingmüller, Ursula; Anderhub, Simon; Ho, A. D.; Krämer, Alwin

doi:10.1038/leu.2011.283

Cited by 8 publications

(10 citation statements)

References 47 publications

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“…We note that this contradicts previous findings that addition of PACT to PDGFRα or PDGFRβ, kinases found in MPN centrosome-kinase fusions, is not sufficient to cause proliferation of BaF3 cells [21]. This discrepancy may be due to differences in experimental design.…”

Section: Discussioncontrasting

confidence: 97%

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Centrosome-Kinase Fusions Promote Oncogenic Signaling and Disrupt Centrosome Function in Myeloproliferative Neoplasms

et al. 2014

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Chromosomal translocations observed in myeloproliferative neoplasms (MPNs) frequently fuse genes that encode centrosome proteins and tyrosine kinases. This causes constitutive activation of the kinase resulting in aberrant, proliferative signaling. The function of centrosome proteins in these fusions is not well understood. Among others, kinase centrosome localization and constitutive kinase dimerization are possible consequences of centrosome protein-kinase fusions. To test the relative contributions of localization and dimerization on kinase signaling, we targeted inducibly dimerizable FGFR1 to the centrosome and other subcellular locations and generated a mutant of the FOP-FGFR1 MPN fusion defective in centrosome localization. Expression in mammalian cells followed by western blot analysis revealed a significant decrease in kinase signaling upon loss of FOP-FGFR1 centrosome localization. Kinase dimerization alone resulted in phosphorylation of the FGFR1 signaling target PLCγ, however levels comparable to FOP-FGFR1 required subcellular targeting in addition to kinase dimerization. Expression of MPN fusion proteins also resulted in centrosome disruption in epithelial cells and transformed patient cells. Primary human MPN cells showed masses of modified tubulin that colocalized with centrin, Smoothened (Smo), IFT88, and Arl13b. This is distinct from acute myeloid leukemia (AML) cells, which are not associated with centrosome-kinase fusions and had normal centrosomes. Our results suggest that effective proliferative MPN signaling requires both subcellular localization and dimerization of MPN kinases, both of which may be provided by centrosome protein fusion partners. Furthermore, centrosome disruption may contribute to the MPN transformation phenotype.

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Section: Discussioncontrasting

confidence: 97%

“…Targeting of the PDGFRα and PDGFRβ catalytic domains to the centrosome using the PACT domain [20] did not enhance oncogenicity as assayed by IL-3 independent growth of BaF3 cells, a mouse bone marrow-derived cell line [21]. However, it is possible that dimerization is required in concert with localization.…”

Section: Introductionmentioning

confidence: 92%

Centrosome-Kinase Fusions Promote Oncogenic Signaling and Disrupt Centrosome Function in Myeloproliferative Neoplasms

et al. 2014

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“…The fusion genes of patients 1 and 3 lack the TM domain anchoring PDGFRB to the membrane, which may result in delocalization of the fusion protein to the cytoplasm or the nucleus. Although, centrosomal localization does not seem to contribute to oncogenicity (Bochtler et al, ), dislocalization may influence clinical characteristics such as the morphologic phenotype and the clinical course. In addition, CCDC88C harbors a coiled‐coil domain, facilitating dimerization and constitutive activation of the fusion protein.…”

Section: Discussionmentioning

confidence: 99%

Identification and functional characterization of imatinib‐sensitive DTD1‐PDGFRB and CCDC88C‐PDGFRB fusion genes in eosinophilia‐associated myeloid/lymphoid neoplasms

Gosenca

Kellert

Metzgeroth

et al. 2014

Genes Chromosomes & Cancer

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Eosinophilia-associated myeloid neoplasms with rearrangement of chromosome bands 5q31-33 are frequently associated with PDGFRB fusion genes, which are exquisitely sensitive to treatment with imatinib. In search for novel fusion partners of PDGFRB, we analyzed three cases with translocation t(5;20)(q33;p11), t(5;14)(q33;q32), and t(5;17;14)(q33;q11;q32) by 5′-rapid amplification of cDNA ends polymerase chain reaction (5′-RACE-PCR) and DNA-based long-distance inverse PCR (LDI-PCR) with primers derived from PDGFRB. LDI-PCR revealed a fusion between CCDC88C exon 25 and PDGFRB exon 11 in the case with t(5;17;14)(q33;q11;q32) while 5′-RACE-PCR identified fusions between CCDC88C exon 10 and PDGFRB exon 12 and between DTD1 exon 4 and PDGFRB exon 12 in the cases with t(5;14)(q33;q32) and t(5;20)(q33;p11), respectively. The PDGFRB tyrosine-kinase domain is predicted to be retained in all three fusion proteins. The partner proteins contained coiled-coil domains or other domains, which putatively lead to constitutive activation of the PDGFRB fusion protein. In vitro functional analyses confirmed transforming activity and imatinib-sensitivity of the fusion proteins. All three patients achieved rapid and durable complete hematologic remissions on imatinib.

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“…Along with PCM1, several tyrosine kinase gene fusion partners physiologically operate at the centrosome. However, speculation that the resultant hybrid proteins promote neoplasia thereat has been challenged since centrosomal targeting by artificial fusion kinases leaves transforming potential unaffected [6]. PCM1 may instead function tumorigenically by inducing JAK2 oligomerization via its coiled coil domains which in the fusion protein remain largely intact…”

Section: Introductionmentioning

confidence: 99%

t(8;9)(p22;p24)/PCM1-JAK2 Activates SOCS2 and SOCS3 via STAT5

et al. 2013

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Fusions of the tyrosine kinase domain of JAK2 with multiple partners occur in leukemia/lymphoma where they reportedly promote JAK2-oligomerization and autonomous signalling, Affected entities are promising candidates for therapy with JAK2 signalling inhibitors. While JAK2-translocations occur in myeloid, B-cell and T-cell lymphoid neoplasms, our findings suggest their incidence among the last group is low. Here we describe the genomic, transcriptional and signalling characteristics of PCM1-JAK2 formed by t(8;9)(p22;p24) in a trio of cell lines established at indolent (MAC-1) and aggressive (MAC-2A/2B) phases of a cutaneous T-cell lymphoma (CTCL). To investigate signalling, PCM1-JAK2 was subjected to lentiviral knockdown which inhibited 7 top upregulated genes in t(8;9) cells, notably SOCS2/3. SOCS3, but not SOCS2, was also upregulated in a chronic eosinophilic leukemia bearing PCM1-JAK2, highlighting its role as a central signalling target of JAK2 translocation neoplasia. Conversely, expression of GATA3, a key T-cell developmental gene silenced in aggressive lymphoma cells, was partially restored by PCM1-JAK2 knockdown. Treatment with a selective JAK2 inhibitor (TG101348) to which MAC-1/2A/2B cells were conspicuously sensitive confirmed knockdown results and highlighted JAK2 as the active moiety. PCM1-JAK2 signalling required pSTAT5, supporting a general paradigm of STAT5 activation by JAK2 alterations in lymphoid malignancies. MAC-1/2A/2B - the first JAK2–translocation leukemia/lymphoma cell lines described - display conspicuous JAK/STAT signalling accompanied by T-cell developmental and autoimmune disease gene expression signatures, confirming their fitness as CTCL disease models. Our data support further investigation of SOCS2/3 as signalling effectors, prognostic indicators and potential therapeutic targets in cancers with JAK2 rearrangements.

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Centrosomal targeting of tyrosine kinase activity does not enhance oncogenicity in chronic myeloproliferative disorders

Cited by 8 publications

References 47 publications

Centrosome-Kinase Fusions Promote Oncogenic Signaling and Disrupt Centrosome Function in Myeloproliferative Neoplasms

Centrosome-Kinase Fusions Promote Oncogenic Signaling and Disrupt Centrosome Function in Myeloproliferative Neoplasms

Identification and functional characterization of imatinib‐sensitive DTD1‐PDGFRB and CCDC88C‐PDGFRB fusion genes in eosinophilia‐associated myeloid/lymphoid neoplasms

t(8;9)(p22;p24)/PCM1-JAK2 Activates SOCS2 and SOCS3 via STAT5

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