The histone deacetylase inhibitor ITF2357 selectively targets cells bearing mutated JAK2V617F

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 lM), 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.

Evidence and expertise in the management of polycythemia vera and essential thrombocythemia

“…[77][78][79][80][81][82][83] Preliminary data indicate that at least some of these small molecules inhibit cell growth that is dependent on constitutive JAK2/STAT signaling, preferentially suppress growth of progenitors carrying JAK-activating mutations and show significant clinical activity. Thus, these drugs hold promise as molecularly targeted agents for the therapy of patients with MPNs.…”

“…Indications for the use of these new drugs are critically dependent on their expected hematological and extra-hematological toxicity. JAK2 inhibitors with limited side effects, such as ITF2357, a histone deacetylase inhibitor, 78 can be proposed for patients with PV and/or ET provided they need therapy. However, more toxic agents should be reserved for patients with intermediate or high-risk primary and post-PV/ET myelofibrosis, given the significant disease-related morbidity and the poor prognosis in this setting.…”

Chronic myeloproliferative diseases with and without the Ph chromosome: some unresolved issues

“…82 In vitro, the drug significantly reduced proliferation of JAK2 V617F mutated cells, including endogenous erythroid colony formation, through the post-transcriptional downregulation of JAK2. 83 Orchestrating gene expression in normal adult cells and during development is one role of microRNAs (miRNAs), which is a large family of small non-coding RNAs. However, miRNAs can also function either as oncogenes or oncosuppressors 84 in human cancer, including acute or chronic leukemias.…”

Aberrant signal transduction pathways in myeloproliferative neoplasms

“…Recently, encouraging results were obtained with an HDAC (histone deacetylase) inhibitor, which seems to target only JAK2 V617F-positive cells among primary myeloid progenitors from PV patients. 149 Thus, like other cancers, 150 MPNs might also show restriction of fate options through hypermethylation. This notion is supported by the different effects of sequential treatment with the DNA methyltransferase inhibitor, decitabine, followed by the histone deacetylase inhibitor, trichostatin A (TSA), on normal CD34( þ ) versus PMF CD34( þ ) cells.…”