Showing papers by "Jerome Tamburini published in 2014"
TL;DR: In the 78 patients who received allogeneic hematopoietic stem cell transplantation in CR2, GO before transplant significantly improved posttransplant DFS and OS without excess of treatment-related mortality.
57 citations
TL;DR: Patients with AML cell resistance against PI3K‐mTOR inhibitors showed increased mRNA expression of the CDC25B gene that encodes the cell cycle regulator Cell Division Cycle 25B, which is known to crosstalk with the PI3k‐Akt‐m TOR pathway and mediate rapamycin resistance in experimental models.
Abstract: Acute myeloid leukaemia (AML) is a heterogeneous malignancy. Intracellular signalling through the phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) pathway is important for regulation of cellular growth and metabolism, and inhibitors of this pathway is considered for AML treatment. Primary human AML cells, derived from 96 consecutive adult patients, were examined. The effects of two mTOR inhibitors (rapamycin, temsirolimus) and two PI3K inhibitors (GDC-0941, 3-methyladenine) were studied, and we investigated cytokine-dependent proliferation, regulation of apoptosis and global gene expression profiles. Only a subset of patients demonstrated strong antiproliferative effects of PI3K-mTOR inhibitors. Unsupervised hierarchical clustering analysis identified two main clusters of patients; one subset showing weak or absent antiproliferative effects (59%) and another group showing a strong growth inhibition for all drugs and concentrations examined (41%). Global gene expression analyses showed that patients with AML cell resistance against PI3K-mTOR inhibitors showed increased mRNA expression of the CDC25B gene that encodes the cell cycle regulator Cell Division Cycle 25B. The antileukaemic effect of PI3K-Akt-mTOR inhibition varies between patients, and resistance to these inhibitors is associated with the expression of the cell cycle regulator CDC25B, which is known to crosstalk with the PI3K-Akt-mTOR pathway and mediate rapamycin resistance in experimental models.
37 citations
TL;DR: A new pathway involved in the resistance of FLT3-ITD leukemic cells to genotoxic agents is identified, and the first report of CHK1 Ser 280 regulation in myeloid malignancies is reported.
Abstract: Phosphorylation by Akt on Ser 280 was reported to induce cytoplasmic retention and inactivation of CHK1 with consequent genetic instability in PTEN−/− cells. In acute myeloid leukemia cells carrying the FLT3-internal tandem duplication (ITD) mutation, we observed high rates of FLT3-ITD-dependent CHK1 Ser 280 phosphorylation. Pharmacological inhibition and RNA interference identified Pim1/2, not Akt, as effectors of this phosphorylation. Pim1 catalyzed Ser 280 phosphorylation in vitro and ectopic expression of Pim1/2-induced CHK1 phosphorylation. Ser 280 phosphorylation did not modify CHK1 localization, but facilitated its cell cycle and resistance functions in leukemic cells. FLT3, PIM or CHK1 inhibitors synergized with DNA-damaging agents to induce apoptosis, allowing cells to bypass the etoposide-induced G2/M arrest. Consistently, etoposide-induced CHK1-dependent phosphorylations of CDC25C on Ser 216 and histone H3 on Thr11 were decreased upon FLT3 inhibition. Accordingly, ectopic expression of CHK1 improved the resistance of FLT3-ITD cells and maintained histone H3 phosphorylation in response to DNA damage, whereas expression of unphosphorylated Ser 280Ala mutant did not. Finally, FLT3- and Pim-dependent phosphorylation of CHK1 on Ser 280 was confirmed in primary blasts from patients. These results identify a new pathway involved in the resistance of FLT3-ITD leukemic cells to genotoxic agents, and they constitute the first report of CHK1 Ser 280 regulation in myeloid malignancies.
36 citations
TL;DR: L-ase kills leukemic cells by depleting circulating asparagine pools related to its asparaginase activator by exploiting the reprograming of T-lymphocytes to secrete polypeptide A in a “spatially aggregating” manner.
Abstract: l-asparaginase (L-ase) is a major drug used to treat acute lymphoblastic leukemia (ALL) [1]. L-ase kills leukemic cells by depleting circulating asparagine pools related to its asparaginase activit...
29 citations
TL;DR: The data identify CHK1 as a regulator of FLT3-ITD-positive leukemic cells proliferation, and they open interesting perspectives in terms of new therapeutic strategies for these pathologies, as well as revealing no accumulation in a specific phase of the cell cycle uponCHK1 inhibition.
22 citations
TL;DR: The data suggest that GNB1 mutations can promote tumorigenesis in more than one cell lineage, as observed in patients and in vivo treatment of the myeloid neoplasm with the dual PI3K/mTOR inhibitor BEZ235 suppressed GNB 1-induced signaling and markedly increased survival.
3 citations
TL;DR: The results suggested that the TKI resistant clones could be effectively targeted by PLK1 inhibition, providing an insight to the design of combination treatment with FLT3 inhibitors inFLT3-ITD+ AML.
1 citations
TL;DR: It is reported that sustained mTORC1 activity is nonetheless essential for the cytotoxicity induced by pharmacologic activation of AMP-activated protein kinase (AMPK) in AML, and this finding may have important implications for AMPK and m TORC1 signaling pathways in cancer biology more broadly.
1 citations
TL;DR: A 76-year-old man was referred to our hospital in October 2012 for the exploration of white cell count abnormalities as mentioned in this paper. He had a history of seropositive generalized myasthenia gravis (MG) with anti-a...
Abstract: A 76-year-old man was referred to our hospital in October 2012 for the exploration of white cell count abnormalities. He had a history of seropositive generalized myasthenia gravis (MG) with anti-a...
TL;DR: The general concept of targeting signaling pathways in cancers and the limitations of this strategy are discussed, with a particular focus on the emergence of resistant cancer clones under the selective pressures exerted by targeted therapies.
Abstract: SUMMARY Until recently, the treatment of blood cancers has rested exclusively on chemotherapy, radiation and, in select cases, stem cell transplantation, giving rise to frequent and sometimes life-threatening side effects. The past 10 years have witnessed dramatic clinical advances due to the development of novel therapies, hereafter referred to as targeted therapies, which specifically inhibit molecules that are essential to the pathophysiology of individual malignancies. In this article, we will discuss the general concept of targeting signaling pathways in cancers and the limitations of this strategy, with a particular focus on the emergence of resistant cancer clones under the selective pressures exerted by targeted therapies. Finally, we will examine a number of targeted therapies with immediate application in contemporary clinical practice.