Publications by authors named "Federica Mezzasoma"

Article Synopsis
  • The EVI1 gene is linked to a particularly aggressive form of acute myeloid leukemia (AML) characterized by abnormalities on chromosome 3q26.
  • Selective and pan-histone deacetylase inhibitors (HDACis) have been identified as effective treatments for this type of leukemia by repressing EVI1 expression.
  • The study suggests that the PA2G4 protein plays a key role in EVI1-related leukemia, and targeting PA2G4 could enhance the effects of HDACis, highlighting the potential for combination therapies in patients with 3q26 AML.
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Article Synopsis
  • - Acute myeloid leukemia (AML) poses a significant treatment challenge for both adult and pediatric patients, with CAR T-cell therapy showing promise but needing further refinement for safe and lasting results, particularly for older patients.
  • - Current CAR T-cell therapies are hindered by the lack of a perfect tumor-specific antigen, as key targets CD123 and CD33 are also present on healthy cells, risking harmful side effects.
  • - A new dual-CAR approach using cytokine-induced killer (CIK) cells, designed to target CD123 and CD33 while minimizing damage to normal cells, has shown effective antitumor responses in AML without causing major toxicity.
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NPM1 is the most frequently mutated gene in adults with acute myeloid leukemia (AML). The interaction between mutant NPM1 (NPM1c) and exportin-1 (XPO1) causes aberrant cytoplasmic dislocation of NPM1c and promotes the high expression of homeobox (HOX) genes, which is critical for maintaining the leukemic state of NPM1-mutated cells. Although there is a rationale for using XPO1 inhibitors in NPM1-mutated AML, selinexor administered once or twice per week did not translate into clinical benefit in patients with NPM1 mutations.

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The administration of combinations of drugs is a method widely used in the treatment of different pathologies as it can lead to an increase in the therapeutic effect and a reduction in the dose compared to the administration of single drugs. For these reasons, it is of interest to study combinations of drugs and to determine whether a specific combination has a synergistic, antagonistic or additive effect. Various mathematical models have been developed, which use different methods to evaluate the synergy of a combination of drugs.

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Nucleophosmin (NPM1) mutations in acute myeloid leukemia (AML) affect exon 12, but also sporadically affect exons 9 and 11, causing changes at the protein C-terminal end (tryptophan loss, nuclear export signal [NES] motif creation) that lead to aberrant cytoplasmic NPM1 (NPM1c+), detectable by immunohistochemistry. Combining immunohistochemistry and molecular analyses in 929 patients with AML, we found non-exon 12 NPM1 mutations in 5 (1.3%) of 387 NPM1c+ cases.

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Article Synopsis
  • Acute myeloid leukemia (AML) with NPM1 mutations is prevalent but challenging to treat, especially in elderly and unfit patients who can't tolerate intensive therapies.
  • Dactinomycin, a low-cost chemotherapy, shows promise in inducing complete responses in relapsed/refractory NPM1-mutated AML based on a pilot study, highlighting its safety and efficacy.
  • The drug's effectiveness may be linked to its ability to create nucleolar stress, which appears to particularly affect cells with NPM1 mutations, indicating a need for further large-scale research.
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-mutated (mut) acute myeloid leukemia (AML) comprises about 30% of newly diagnosed AML in adults. Despite notable advances in the treatment of this frequent AML subtype, about 50% of mut AML patients treated with conventional treatment die due to disease progression. CD123 has been identified as potential target for immunotherapy in AML, and several anti-CD123 therapeutic approaches have been developed for AML resistant to conventional therapies.

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Purpose: Ibrutinib, a Bruton tyrosine kinase inhibitor (BTKi), has improved the outcomes of chronic lymphocytic leukemia (CLL), but primary resistance or relapse are issues of increasing significance. While the predominant mechanism of action of BTKi is the B-cell receptor (BCR) blockade, many off-target effects are unknown. We investigated potential interactions between BCR pathway and NOTCH1 activity in ibrutinib-treated CLL to identify new mechanisms of therapy resistance and markers to monitor disease response.

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As previously reported, chronic lymphocytic leukemia (CLL) cells show constitutive Notch1/2 activation and express the Notchligand Jagged1. Despite increasing knowledge of the impact of Notch alterations on CLL biology and pathogenesis, the role of Jagged1 expressed in CLL cells remains undefined. In other cell types, it has been shown that after Notch engagement, Jagged1 not only activates Notch in signal-receiving cell, but also undergoes proteolytic activation in signal-sending cell, triggering a signaling with biological effects.

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NPM1 is the most frequently mutated gene in cytogenetically normal acute myeloid leukemia (AML). In AML cells, NPM1 mutations result in abnormal cytoplasmic localization of the mutant protein (NPM1c); however, it is unknown whether NPM1c is required to maintain the leukemic state. Here, we show that loss of NPM1c from the cytoplasm, either through nuclear relocalization or targeted degradation, results in immediate downregulation of homeobox (HOX) genes followed by differentiation.

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Nucleophosmin (NPM1) mutations represent an attractive therapeutic target in acute myeloid leukemia (AML) because they are common (∼30% AML), stable, and behave as a founder genetic lesion. Oncoprotein targeting can be a successful strategy to treat AML, as proved in acute promyelocytic leukemia by treatment with all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO), which degrade the promyelocytic leukemia (PML)-retinoic acid receptor fusion protein. Adjunct of ATRA to chemotherapy was reported to be beneficial for NPM1-mutated AML patients.

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Acute myeloid leukemia (AML) with mutated NPM1 shows distinctive biologic and clinical features, including absent/low CD34 expression, the significance of which remains unclear. Therefore, we analyzed CD34(+) cells from 41 NPM1-mutated AML. At flow cytometry, 31 of 41 samples contained less than 10% cells showing low intensity CD34 positivity and variable expression of CD38.

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