Acute myeloid leukemia with mutated nucleophosmin (NPM1): Any hope for a targeted therapy?

Falini, Brunangelo; Gionfriddo, Ilaria; Cecchetti, Federica; Ballanti, Stelvio; Pettirossi, Valentina; Martelli, Maria Paola

doi:10.1016/j.blre.2011.06.001

Cited by 71 publications

(65 citation statements)

References 113 publications

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“…This is not surprising considering the fact that LSAs are formed by genetic alterations (chromosomal translocations or gene mutations) that are causally involved in leukemogenesis. [50][51][52][53][54] Several LAAs have also been implicated in the multi-step leukemic transformation of hematopoietic progenitor cells, for example, ETO/MTG8, 55 hTERT 56 and the homeobox protein HOXA9. 57 The LAA WT1 may contribute to leukemogenesis by interfering with normal hematopoietic progenitor cell differentiation, which is considered as one of the first critical steps in the leukemic transformation of these cells.…”

Section: Leukemogenesismentioning

confidence: 99%

Leukemia-associated antigens and their relevance to the immunotherapy of acute myeloid leukemia

2012

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The graft-versus-leukemia effect of allogeneic hematopoietic stem cell transplantation (HSCT) has shown that the immune system is capable of eradicating acute myeloid leukemia (AML). This knowledge, along with the identification of the target antigens against which antileukemia immune responses are directed, has provided a strong impetus for the development of antigen-targeted immunotherapy of AML. The success of any antigen-specific immunotherapeutic strategy depends critically on the choice of target antigen. Ideal molecules for immune targeting in AML are those that are: (1) leukemia-specific; (2) expressed in most leukemic blasts including leukemic stem cells; (3) important for the leukemic phenotype; (4) immunogenic; and (5) clinically effective. In this review, we provide a comprehensive overview on AML-related tumor antigens and assess their applicability for immunotherapy against the five criteria outlined above. In this way, we aim to facilitate the selection of appropriate target antigens, a task that has become increasingly challenging given the large number of antigens identified and the rapid pace at which new targets are being discovered. The information provided in this review is intended to guide the rational design of future antigen-specific immunotherapy trials, which will hopefully lead to new antileukemia therapies with more selectivity and higher efficacy.

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Section: Leukemogenesismentioning

confidence: 99%

Leukemia-associated antigens and their relevance to the immunotherapy of acute myeloid leukemia

2012

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“…1 Mutations in exon 12 of the NPM1 gene are the most common genetic alterations in cytogenetically normal adult acute myelogenous leukemia (AML) patients, and are responsible for the aberrant cytoplasmic localization of NPM1 COOH terminal mutations (NPMc þ ). NPMc þ defines a distinct leukemia subset with a relatively favorable prognosis, [2][3][4] although an explanation for why individuals with this subset of acute leukemia respond to therapy more favorably is lacking.…”

Section: Introductionmentioning

confidence: 99%

Role of cysteine 288 in nucleophosmin cytoplasmic mutations: sensitization to toxicity induced by arsenic trioxide and bortezomib

Huang

Thomas

et al. 2013

Leukemia

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Mutations in exon 12 of the nucleophosmin (NPM1) gene (NPMc þ (NPM1 COOH terminal mutations)) define a distinct subset of acute myelogenous leukemias (AMLs), in which the NPMc þ protein localizes aberrantly to the leukemic cell cytoplasm. We have found that introduction of the most common NPMc þ variant into K562 and 32D cells sensitizes these cells to apoptosis induced by drugs such as bortezomib and arsenic trioxide (ATO) that induce reactive oxygen species (ROS) formation, and that cytotoxicity is prevented in the presence of N-acetyl-L-cysteine (NAC), an ROS scavenger. The substitution of tryptophan 288 (W288) by cysteine occurs in the great majority of NPM1c þ mutations. Mutagenesis of cysteine 288 to alanine re-localizes NPMc þ from the cytoplasm to the nucleolus and attenuates the sensitivity of cells expressing this mutation to bortezomib and ATO. Primary AML cells expressing NPMc þ are also significantly more sensitive than other AML cells to apoptosis induced by both drugs at pharmacologically achievable doses. We conclude that the presence of a cysteine moiety at position 288 results in the cytoplasmic localization of NPM1c þ and the increased sensitivity to bortezomib and ATO. These data suggest that bortezomib and ATO may have increased therapeutic efficacy in NPM1c þ leukemias.

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“…Moreover, mutations are always heterozygous in acute myeloid leukemia patients, and mutated NPM1 oligomerizes with the wild-type protein, which is also largely translocated in the cytosol. However, a small amount of wild-type NPM1 still resides at nucleoli of leukemic blasts and contributes to maintain nucleolar integrity and ribosome processing and export capabilities (29). These considerations have led to the suggestion that a possible strategy to specifically target NPM1 in acute myeloid leukemia patients with mutations at the NPM1 gene might be that of depriving leukemic blast nucleoli of residual NPM1, thus causing nucleolar stress and the activation of apoptotic cell death (29).…”

Section: Discussionmentioning

confidence: 99%

Synergic Role of Nucleophosmin Three-helix Bundle and a Flanking Unstructured Tail in the Interaction with G-quadruplex DNA

Arcovito

Chiarella

Longa

et al. 2014

Journal of Biological Chemistry

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Background: Nucleophosmin is a nucleolar protein that interacts with G-quadruplexes. Results: Site-directed mutagenesis and molecular dynamics unravel the role of single residues in complex formation. Conclusion: A disordered segment of nucleophosmin contributes to G-quadruplex recognition by facilitating the formation of an encounter complex and transiently interacting with the G-quadruplex. Significance: Understanding the role played by flanking fuzziness is an important issue in protein/DNA interactions.

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Acute myeloid leukemia with mutated nucleophosmin (NPM1): Any hope for a targeted therapy?

Cited by 71 publications

References 113 publications

Leukemia-associated antigens and their relevance to the immunotherapy of acute myeloid leukemia

Leukemia-associated antigens and their relevance to the immunotherapy of acute myeloid leukemia

Role of cysteine 288 in nucleophosmin cytoplasmic mutations: sensitization to toxicity induced by arsenic trioxide and bortezomib

Synergic Role of Nucleophosmin Three-helix Bundle and a Flanking Unstructured Tail in the Interaction with G-quadruplex DNA

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