AI Article Synopsis

  • ITF2357 is a new histone deacetylase inhibitor (HDACi) that shows promising antitumor effects specifically on cells with the JAK2(V617F) mutation found in patients with polycythemia vera and essential thrombocythemia.
  • The compound significantly inhibits the clonogenic activity of mutated cells at very low concentrations (IC(50) 0.001-0.01 microM), promoting the growth of unmutated over mutated colonies by a factor of seven.
  • ITF2357 effectively reduces both the JAK2(V617F) protein and its signaling pathways without affecting the wild-type JAK2 or other STAT proteins in healthy control cells, highlighting its targeted action against

Article Abstract

We investigated the activity of ITF2357, a novel histone deacetylase inhibitor (HDACi) with antitumor activity, on cells carrying the JAK2(V617F) mutation obtained from polycythemia vera (PV) and essential thrombocythemia (ET) patients as well as the HEL cell line. The clonogenic activity of JAK2(V617F) mutated cells was inhibited by low concentrations of ITF2357 (IC(50) 0.001-0.01 microM), 100- to 250-fold lower than required to inhibit growth of normal or tumor cells lacking this mutation. Under these conditions, ITF2357 allowed a seven fold increase in the outgrowth of unmutated over mutated colonies. By western blotting we showed that in HEL cells, ITF2357 led to the disappearance of total and phosphorylated JAK2(V617F) as well as pSTAT5 and pSTAT3, but it did not affect the wild-type JAK2 or STAT proteins in the control K562 cell line. By real-time PCR, we showed that, upon exposure to ITF2357, JAK2(V617F) mRNA was not modified in granulocytes from PV patients while the expression of the PRV-1 gene, a known target of JAK2, was rapidly downmodulated. Altogether, the data presented suggest that ITF2357 inhibits proliferation of cells bearing the JAK2(V617F) mutation through a specific downmodulation of the JAK2(V617F) protein and inhibition of its downstream signaling.

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Source
http://dx.doi.org/10.1038/sj.leu.2405049DOI Listing

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