INT113160

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Context Info
Confidence 0.58
First Reported 2003
Last Reported 2009
Negated 1
Speculated 2
Reported most in Body
Documents 26
Total Number 28
Disease Relevance 20.30
Pain Relevance 2.57

This is a graph with borders and nodes. Maybe there is an Imagemap used so the nodes may be linking to some Pages.

cell differentiation (Jak2) cytosol (Jak2) signal transduction (Jak2)
histone binding (Jak2) cytoskeleton (Jak2) nucleus (Jak2)
Anatomy Link Frequency
spleen 1
reticulocyte 1
hippocampus 1
Jak2 (Mus musculus)
Jak2 - V617F (2)
Pain Link Frequency Relevance Heat
Hippocampus 27 100.00 Very High Very High Very High
GABAergic 13 99.30 Very High Very High Very High
Inflammation 86 98.84 Very High Very High Very High
Bioavailability 19 98.68 Very High Very High Very High
gABA 28 95.88 Very High Very High Very High
tetrodotoxin 2 91.64 High High
cytokine 99 91.24 High High
fibrosis 69 91.16 High High
COX-2 inhibitor 1 90.40 High High
antagonist 5 88.08 High High
Disease Link Frequency Relevance Heat
Myelofibrosis 421 99.80 Very High Very High Very High
Myeloproliferative Disorder 338 99.78 Very High Very High Very High
Myelodysplastic Syndromes 1204 99.72 Very High Very High Very High
Disease Progression 52 99.44 Very High Very High Very High
Reticulocytosis 42 99.14 Very High Very High Very High
Disease 309 98.98 Very High Very High Very High
INFLAMMATION 94 98.84 Very High Very High Very High
Erythrocytosis 372 98.74 Very High Very High Very High
Myeloid Leukemia 344 97.82 Very High Very High Very High
Congenital Anomalies 122 96.20 Very High Very High Very High

Sentences Mentioned In

Key: Protein Mutation Event Anatomy Negation Speculation Pain term Disease term
By analogy to CML, if PV is caused directly by JAK2 V617F, then the disease should be exquisitely sensitive to small molecule inhibitors of JAK2.
Negative_regulation (inhibitors) of JAK2 associated with myeloid leukemia, myelodysplastic syndromes and disease
1) Confidence 0.58 Published 2006 Journal PLoS ONE Section Body Doc Link PMC1762384 Disease Relevance 0.88 Pain Relevance 0.04
Others and we have designed specific inhibitors of JAK2 that may be useful therapies for PV, although their benefit over current treatment remains to be demonstrated [25].
Negative_regulation (inhibitors) of JAK2 associated with myelodysplastic syndromes
2) Confidence 0.56 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2749451 Disease Relevance 1.52 Pain Relevance 0.05
Although next generation Abelson kinase inhibitors such as dasatinib or nilotinib may expand the role for these agents in MPDs, targeted inhibition of the mutant kinase JAK2V617F is more likely to make significant therapeutic gains in the classic MPDs of PV, ET, and PMF.



Negative_regulation (inhibition) of JAK2V617F associated with myeloproliferative disorder, myelodysplastic syndromes and myelofibrosis
3) Confidence 0.56 Published 2007 Journal Biologics : Targets & Therapy Section Abstract Doc Link PMC2721304 Disease Relevance 2.31 Pain Relevance 0
What effects can we expect to observe from the inhibition of JAK2 (no medication is likely to strictly inhibit the JAK2V617F)?
Negative_regulation (inhibition) of JAK2
4) Confidence 0.56 Published 2007 Journal Biologics : Targets & Therapy Section Body Doc Link PMC2721304 Disease Relevance 0.23 Pain Relevance 0
Polycythemia and reticulocytosis responded to treatment with imatinib or a JAK2 inhibitor, but were unresponsive to the Src inhibitor dasatinib.


Negative_regulation (inhibitor) of JAK2 associated with reticulocytosis and erythrocytosis
5) Confidence 0.43 Published 2006 Journal PLoS ONE Section Abstract Doc Link PMC1762384 Disease Relevance 1.86 Pain Relevance 0.04
There are no JAK2 inhibitors in clinical use, but the isoquinolinone compound JAK inhibitor I [15], [32] and the tyrphostin AG-490 [33] both inhibited the proliferation of Ba/F3 cells expressing JAK2 V617F with an IC50 of 0.3 and 3.5 ┬ÁM, respectively (Figure 7B).
Neg (no) Negative_regulation (inhibitors) of JAK2
6) Confidence 0.43 Published 2006 Journal PLoS ONE Section Body Doc Link PMC1762384 Disease Relevance 0.29 Pain Relevance 0.07
By contrast, imatinib therapy did cause a significant decrease in hematocrit and reticulocyte counts in JAK2 V617F recipients, and similar responses have been reported in PV patients [31].
Negative_regulation (decrease) of JAK2 V617F (V617F) in reticulocyte associated with myelodysplastic syndromes
7) Confidence 0.43 Published 2006 Journal PLoS ONE Section Body Doc Link PMC1762384 Disease Relevance 0.92 Pain Relevance 0.03
There are no inhibitors of JAK kinases in current clinical use, and existing preclinical JAK2 inhibitors are compromised by lack of oral bioavailability and short in vivo half-life.
Negative_regulation (inhibitors) of JAK2 associated with bioavailability
8) Confidence 0.43 Published 2006 Journal PLoS ONE Section Body Doc Link PMC1762384 Disease Relevance 0.86 Pain Relevance 0.05
However, we provide proof-of-principle that a JAK2 inhibitor should have therapeutic effects on the polycythemia, and perhaps myelofibrosis and hemostatic abnormalities, suffered by MPD patients carrying the JAK2 V617F mutation.



Negative_regulation (inhibitor) of JAK2 associated with congenital anomalies, erythrocytosis and myelofibrosis
9) Confidence 0.43 Published 2006 Journal PLoS ONE Section Abstract Doc Link PMC1762384 Disease Relevance 1.41 Pain Relevance 0.03
These results suggest that imatinib impairs JAK2 V617F-induced erythropoiesis through inhibition of a target other than ABL or c-Kit, and confirm that Src kinases may not be good targets for therapy in PV.
Negative_regulation (impairs) of JAK2 V617F (V617F) associated with myelodysplastic syndromes
10) Confidence 0.42 Published 2006 Journal PLoS ONE Section Body Doc Link PMC1762384 Disease Relevance 0.31 Pain Relevance 0.06
CIMF patients with the JAK2 V617F mutation are clinically distinct from those lacking JAK2 mutation, and have a worse overall prognosis [44].
Negative_regulation (lacking) of JAK2 associated with myelofibrosis
11) Confidence 0.42 Published 2006 Journal PLoS ONE Section Body Doc Link PMC1762384 Disease Relevance 1.75 Pain Relevance 0.05
According to these authors, the observed clinical benefit may be a consequence of KIT rather than JAK2 inhibition.
Negative_regulation (inhibition) of JAK2
12) Confidence 0.42 Published 2007 Journal Intern Emerg Med Section Body Doc Link PMC2780604 Disease Relevance 0.84 Pain Relevance 0.03
Moreover, introduction of JAK2V617F into hematopoietic cells causes PV in mice, and inhibitors of Jak2 (Jak2i's) reduce hematocrit and spleen size [11].
Negative_regulation (inhibitors) of Jak2 in spleen associated with myelodysplastic syndromes
13) Confidence 0.41 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2749451 Disease Relevance 1.78 Pain Relevance 0
Therefore, what impact JAK2 inhibition will have on disease progression (ie, none, decrease, or increase) is quite uncertain and will require close long-term monitoring of patients taking JAK2 inhibitors, to be certain no adverse impact arises from the use of these agents.
Negative_regulation (inhibition) of JAK2 associated with disease progression
14) Confidence 0.41 Published 2007 Journal Biologics : Targets & Therapy Section Body Doc Link PMC2721304 Disease Relevance 0.69 Pain Relevance 0
What effects can we expect to observe from the inhibition of JAK2 (no medication is likely to strictly inhibit the JAK2V617F)?
Spec (likely) Negative_regulation (inhibit) of JAK2V617F
15) Confidence 0.41 Published 2007 Journal Biologics : Targets & Therapy Section Body Doc Link PMC2721304 Disease Relevance 0.23 Pain Relevance 0
There have already been multiple reports of agents in development which have demonstrated the ability to inhibit the aberrant JAK2V617F, along with the wild type JAK2, such as TG101209 (Pardanani, Hood et al 2006), Go6976 (Grandage et al 2006), erlotinib (Li et al 2006), MK0457 (Giles et al 2006), CEP-701 (Dobrzanski et al 2006) (now in a clinical study), and Z3 (Sayyah et al 2006).
Negative_regulation (inhibit) of JAK2V617F
16) Confidence 0.41 Published 2007 Journal Biologics : Targets & Therapy Section Body Doc Link PMC2721304 Disease Relevance 0.42 Pain Relevance 0.06
These latter goals are highly desired but uncertainty exist as to whether the inhibition of JAK2 will accomplish these goals since the exact role of the JAK2V617F mutation in disease progression or development of PMF-BP remains unclear (Mesa et al 2006).
Spec (whether) Negative_regulation (inhibition) of JAK2 associated with myelofibrosis and disease progression
17) Confidence 0.41 Published 2007 Journal Biologics : Targets & Therapy Section Body Doc Link PMC2721304 Disease Relevance 0.51 Pain Relevance 0
Next, although there are many agents that may have ability to inhibit the wild type JAK2, we must proceed with caution as few have desired specificity for the JAK2 itself, let alone the JAK2V617F.
Negative_regulation (inhibit) of JAK2
18) Confidence 0.41 Published 2007 Journal Biologics : Targets & Therapy Section Body Doc Link PMC2721304 Disease Relevance 0.36 Pain Relevance 0.04
Challenges as we enter the era of JAK2 inhibitors for PMF and MPD patients are several.
Negative_regulation (inhibitors) of JAK2 associated with myelofibrosis
19) Confidence 0.41 Published 2007 Journal Biologics : Targets & Therapy Section Body Doc Link PMC2721304 Disease Relevance 0.37 Pain Relevance 0.04
Postsynaptic effects of leptin on GABAergic miniature PSCs were eliminated by inhibiting JAK2/3 (Janus kinase), the tyrosine kinase through which leptin receptors signal.
Negative_regulation (inhibiting) of JAK2 associated with gabaergic
20) Confidence 0.41 Published 2003 Journal J. Neurosci. Section Abstract Doc Link 13679427 Disease Relevance 0 Pain Relevance 0.56

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