Activation of a Drosophila Janus kinase (JAK) causes hematopoietic neoplasia and developmental defects.

Harrison, Douglas A.; Binari, Richard; Nahreini, Theresa Stines; Gilman, Michael; Perrimon, Norbert

doi:10.1002/j.1460-2075.1995.tb07285.x

Cited by 426 publications

(342 citation statements)

References 41 publications

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“…Luo et al (1995) showed that the dominant, gain-of-function mutation hop Tum-1 results from a single amino acid substitution at residue 341 and produces a clonal plasmacyte overproliferation similar to human leukemias. Similar studies by Harrison et al (1995) demonstrated that overexpression of wild-type hop or hop Tum-1 leads to an identical phenotype with tumor formation within the larval lymph glands, which serve as hematopoietic organs in Drosophila. The tumorigenicity of hop or hop Tum-1 overexpression was tissue speci®c, as expression in other tissues did not result in tumor formation.…”

Section: Inappropriate Stat Activation In Leukemiamentioning

confidence: 57%

STAT signaling in the pathogenesis and treatment of leukemias

2000

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Section: Inappropriate Stat Activation In Leukemiamentioning

confidence: 57%

STAT signaling in the pathogenesis and treatment of leukemias

2000

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“…Constitutively active JAKs may be tumorigenic, at least in two settings. First, gain of function mutations in the Drosophila homolog of JAK, hopscotch, can cause tumors in¯ies, indicating that hyperactive JAKs may be oncogenes (Hanratty and Dearolf, 1993;Harrison et al, 1995). Second, a constitutively active form of JAK2, in form of the TEL/JAK 2 fusion product, has been identi®ed in chromosomal translocations found in atypical CML and pre-B cell ALL (Peeters et al, 1997).…”

Section: Biological Significance Of Jak Activation By V-ablmentioning

confidence: 99%

JAK-STAT signaling activated by Abl oncogenes

2000

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“…We have shown previously that overactivation of JAK, which phosphorylates STAT 5,6 , disrupts heterochromatin formation globally in Drosophila melanogaster 7 . However, it remains unclear how this effect is mediated and whether STAT is involved.…”

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confidence: 97%

Drosophila STAT is required for directly maintaining HP1 localization and heterochromatin stability

et al. 2008

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STAT (Signal transducer and activator of transcription) is a potent transcription factor and its aberrant activation by phosphorylation is associated with human cancers [1][2][3][4] . We have shown previously that overactivation of JAK, which phosphorylates STAT 5,6 , disrupts heterochromatin formation globally in Drosophila melanogaster 7 . However, it remains unclear how this effect is mediated and whether STAT is involved. Here, we demonstrate that Drosophila STAT (STAT92E) is involved in controlling heterochromatin protein 1 (HP1) distribution and heterochromatin stability. We found, unexpectedly, that loss of STAT92E, had the same effects as overactivation of JAK in disrupting heterochromatin formation and heterochromatic gene silencing, whereas overexpression of STAT92E had the opposite effects. We have further shown that the unphosphorylated or 'transcriptionally inactive' form of STAT92E is localized on heterochromatin in association with HP1, and is required for stabilizing HP1 localization and histone H3 Lys 9 methylation (H3mK9). However, activation by phosphorylation reduces heterochromatin-associated STAT92E, causing HP1 displacement and heterochromatin destabilization. Thus, reducing levels of unphosphorylated STAT92E, either by loss of STAT92E or increased phosphorylation, causes heterochromatin instability. These results suggest that activation of STAT by phosphorylation controls both access to chromatin and activity of the transcription machinery.To understand the molecular mechanism underlying JAK/STAT-mediated tumour formation, we have previously investigated the role of JAK in a Drosophila leukaemia model, in which a hyperactive mutant form of JAK (Tum-1) causes leukaemia-like overproliferation of blood cells 5,8 . We have demonstrated that oncogenic JAK disrupts heterochromatin formation globally, allowing transcriptional activation of genes that are not necessarily direct targets of STAT 7,9 . The molecular mechanism underlying the effects of Hopscotch (Hop, Drosophila JAK) on heterochromatin remains unclear. It may be mediated by phosphorylation of STAT92E, as in the canonical JAK/STAT pathway 10,11 . Alternatively, Hop may activate cellular targets other than STAT92E 9 .To investigate whether disruption of heterochromatin induced by Hop-activation 7 is mediated by STAT92E, we examined the effects of reducing stat92E + dosage on heterochromatic gene silencing, which can be measured by position-effect variegation (PEV) 12 We next examined the epistatic relationship between HP1 and STAT92E ( Fig. 1d-k). HP1, encoded by Su(var)205, is a constitutive component of heterochromatin and is essential for heterochromatic gene silencing 12,13 . Consistent with the results described above, we found that increasing stat92E + dosage by a chromosomal duplication (referred to as 3 × stat92E + , Fig. 1f) or a stat92E + transgene ( Supplementary Information, Fig. S1) enhanced heterochromatic gene silencing, resulting in complete silencing of the variegated white + gene. This effect was antagonized,...

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Activation of a Drosophila Janus kinase (JAK) causes hematopoietic neoplasia and developmental defects.

Cited by 426 publications

References 41 publications

STAT signaling in the pathogenesis and treatment of leukemias

STAT signaling in the pathogenesis and treatment of leukemias

JAK-STAT signaling activated by Abl oncogenes

Drosophila STAT is required for directly maintaining HP1 localization and heterochromatin stability

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