Enrico Bracco

The NF-kappaB pathway blockade by the IKK inhibitor PS1145 can overcome imatinib resistance.

Imatinib represents at present the most attractive therapy for BCR-ABL positive leukemias, even though a percentage of CML patients develop resistance to this compound. For these resistant patients a therapeutic approach based on a combination of drugs is more likely to be effective. In the last years, constitutive NF-κB/Rel activity has been demonstrated in several hematological malignancies. As a result, NFkB/Rel-blocking approaches have been proposed as antineoplastic strategies. Furthermore, the identification of specific kinases within the NF-κB activation pathway offers a selective target to address tailored therapies. In the current study, we show that the IKK inhibitor PS1145 is able to inhibit the proliferation of CML cell lines and primary BM cells. Moreover, the addition of Imatinib increases the effects of PS1145 in resistant cell lines and BM cells from resistant patients, with a further increase of apoptosis and inhibition of proliferation and colony growth. Our data provide the rational for a new therapeutic approach, which combines Imatinib and the IKK inhibitor PS1145 in CML resistant patients.

Increase sensitivity to chemotherapeutical agents and cytoplasmatic interaction between NPM leukemic mutant and NF-κB in AML carrying NPM1 mutations

Mutations in nucleophosmin (NPM) exon 12 and the resulting delocalization of NPM into the cytoplasm are the most specific and frequent cellular events in acute myeloid leukemia patients (AML) with normal karyotype. Cytoplasmatic NPM (NPMc+) is associated with responsiveness to chemotherapy and better prognosis. The activation of nuclear factor-κB (NF-κB) has been demonstrated to occur in a subset of AML patients and is thought to induce resistance to many chemotherapeutical agents. In this study, we demonstrate the increased in vitro sensitivity of NPMc+ cells to chemotherapeutical agents and their reduced NF-κB activity. Furthermore, we provide evidence of the interaction between NPMc+ and NF-κB in the cytoplasm, resulting in the sequestration and inactivation of NF-κB. The cytosolic localization and consequent inactivation of NF-κB justifies the reduced NF-κB DNA-binding activity observed in NPMc+ patients. These data, taken together, may provide a possible explanation for the increased rate of chemosensitivity observed among the NPMc+ patients.

CD7/CD56-positive acute myeloid leukemias are characterized by constitutive phosphorylation of the NF-kB subunit p65 at Ser536.

CD7/CD56-positive acute myeloid leukemias are characterized by constitutive phosphorylation of the NF-kB subunit p65 at Ser536

Retraction Note to: Increase sensitivity to chemotherapeutical agents and cytoplasmatic interaction between the NPM leukemic mutant and NF-κB in AML carrying NPM1 mutations

The authors of the above article would like to retract it due to an inaccuracy in Figure 5. The remainder of the data presented is sound and fully supports the scientific conclusions of the paper. Dr Francesca Messa, a biologist of the Department of Clinical and Biological Sciences, University of Turin, Turin, Italy, has admitted to intentionally providing false confocal images (Figure 5a and b). Professor G Saglio states categorically that the other authors of this paper were not involved in or aware of these events.