¹Hematology Unit, Ospedali Riuniti, Bergamo, Italy

Correspondence: Professor A Rambaldi, USC Hematology, Ospedali Riuniti, Largo Barozzi 1, Bergamo 24128, Italy. E-mail: arambaldi@ospedaliriuniti.bergamo.it

Received 20 September 2007; Revised 31 October 2007; Accepted 5 November 2007; Published online 13 December 2007.

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 (IC₅₀ 0.001–0.01 M), 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.