Characterization of the Philadelphia chromosome by gene mapping

1981 ◽  
Vol 30 (2) ◽  
pp. 83-91 ◽  
Author(s):  
Geurts van Kessel ◽  
H. ten Brinke ◽  
W.A.M. Boere ◽  
W.C. den Boer ◽  
P.G. de Groot ◽  
...  
Keyword(s):  
Gene Mapping ◽  
Philadelphia Chromosome

Characterization of a complex philadelphia translocation (1p-;9q+;22q-) by gene mapping

1981 ◽  
Vol 58 (2) ◽  
pp. 162-165 ◽  
Author(s):  
A. H. M. Geurts van Kessel ◽  
A. J. van Agthoven ◽  
P. G. de Groot ◽  
A. Hagemeijer
Keyword(s):  
Gene Mapping

Identification and characterization of C3orf6, a new conserved human gene mapping to chromosome 3q28

Gene ◽  
2003 ◽  
Vol 314 ◽  
pp. 113-120 ◽  
Author(s):  
G. Vazza ◽  
S. Picelli ◽  
A. Bozzato ◽  
M.L. Mostacciuolo
Keyword(s):  
Gene Mapping ◽  
Human Gene ◽  
Human Gene Mapping ◽  
Identification And Characterization

Characterization of EST-derived microsatellites for gene mapping and evolutionary genomics in turbot

2008 ◽  
Vol 39 (6) ◽  
pp. 666-670 ◽  
Author(s):  
C. Bouza ◽  
M. Hermida ◽  
A. Millán ◽  
R. Vilas ◽  
M. Vera ◽  
...  
Keyword(s):  
Gene Mapping ◽  
Evolutionary Genomics

Discovery and Preclinical Characterization of INCB018424, a Selective JAK2 Inhibitor for the Treatment of Myeloproliferative Disorders.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3538-3538 ◽  
Author(s):  
Jordan Fridman ◽  
Roberto Nussenzveig ◽  
Phillip Liu ◽  
James Rodgers ◽  
Timothy Burn ◽  
...  
Keyword(s):  
Cell Model ◽  
Ex Vivo ◽  
Philadelphia Chromosome ◽  
Myeloproliferative Disorders ◽  
Janus Kinase ◽  
Great Promise ◽  
Erythroid Progenitors ◽  
Erythroid Progenitor ◽  
Activating Mutations

Abstract Activating mutations in Janus kinase 2 (JAK2) have recently been identified in the majority of Philadelphia chromosome negative (Ph-) myeloproliferative disorders (MPDs). Importantly, constitutive JAK2 activation is oncogenic and, in murine models, recapitulates much of the pathobiology observed in MPD patients, suggesting that JAK2 inhibition may be of therapeutic benefit. Here we describe the identification and preclinical characterization of INCB018424, a potent, selective, and orally bioavailable inhibitor of the JAK2 now in clinical trials. INCB018424 was identified through an extensive medicinal chemistry effort designed to optimize potency, selectivity, pharmaceutical and pharmacokinetic properties. INCB018424 inhibits JAK2 at <1 nM and demonstrated >500–fold selectivity against a broad sampling of the kinome. The potency and selectivity of INCB018424 translated to exceptional cellular activity where it inhibited the proliferation of FDCP cells and BaF/3 cells expressing JAK2V617F with an IC50 of 100–130 nM, but not the proliferation of cell lines expressing activating mutations in either BCR-Abl or cKit (IC50 > 25 and 4 mM, respectively). The effect of INCB18424 on cell proliferation correlated well with reduced levels of phosphorylated JAK2 and STAT5 in the BaF/3 cell model, suggesting that the effect is mediated by pharmacological inhibition of JAK-STAT pathway. Interestingly, the activation of endogenous wild-type JAKs - by the addition of IL-3 - shifted the potency of INCB018424 in the BaF/3 model greater than five fold suggesting that cells expressing the mutated form of JAK2 may be more sensitive to INCB018424. Indeed, using cells harvested from patients with Jak2V617F-positive polycythemia vera (PV) in colony forming assays, we observed that INCB018424 inhibited the cytokine-independent formation of erythroid progenitor colonies (n=3) with an IC50 of 67nM while normal colony formation from healthy donors (n=3) was inhibited 50% at > 400 nM. Further, INCB018424 inhibited proliferation of PV patient samples (n=3) following ex vivo expansion of erythroid progenitors in serum free media, with an IC50 of 60 nM, similar to that observed in semi-solid media. In a mouse model of MPD, where implantation of BaF/3 cells expressing JAK2V617F results in rapid organomegaly and reduced survival, oral administration of INCB018424 was well tolerated and markedly reduced the splenomegaly. Using this animal model, we also demonstrated that selective JAK inhibition eliminates neoplastic cells from the spleen, liver, and bone marrow normalizing the histology of affected organs and significantly prolongs survival. As such, potent and selective JAK inhibitors such as INCB018424 hold great promise for the treatment of MPDs and other disease states associated with elevated JAK activity - a concept currently being tested clinically.

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