Publications by authors named "Ilaria Gionfriddo"

How hematopoietic stem and progenitor cell (HSPC) fate decisions are affected by genetic alterations acquired during AML leukemogenesis is poorly understood and mainly explored in animal models. Here, we study () gene mutations in the human model of HSPC and discuss the available literature on this topic. mutations occur in ~20% of AML cases, are recognized among the mutations earliest acquired during leukemogenesis, and are targets of specific inhibitors (ivosidenib and enasidenib, respectively).

View Article and Find Full Text PDF

Nucleophosmin 1 (NPM1) is a nucleus-cytoplasmic shuttling protein which is predominantly located in the nucleolus and exerts multiple functions, including regulation of centrosome duplication, ribosome biogenesis and export, histone assembly, maintenance of genomic stability and response to nucleolar stress. NPM1 mutations are the most common genetic alteration in acute myeloid leukemia (AML), detected in about 30-35% of adult AML and more than 50% of AML with normal karyotype. Because of its peculiar molecular and clinico-pathological features, including aberrant cytoplasmic dislocation of the NPM1 mutant and wild-type proteins, lack of involvement in driving clonal hematopoiesis, mutual exclusion with recurrent cytogenetic abnormalities, association with unique gene expression and micro-RNA profiles and high stability at relapse, NPM1-mutated AML is regarded as a distinct genetic entity in the World Health Organization (WHO) classification of hematopoietic malignancies.

View Article and Find Full Text PDF

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.

View Article and Find Full Text PDF

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.

View Article and Find Full Text PDF
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.
View Article and Find Full Text PDF

-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.

View Article and Find Full Text PDF

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.

View Article and Find Full Text PDF

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.

View Article and Find Full Text PDF

The NPM1 mutation is the most frequent genetic alteration thus far identified in acute myeloid leukemia (AML). Despite progress in the clinical and biological characterization of NPM1-mutated AML, the role of NPM1 mutation in leukemogenesis in vivo has not been fully elucidated. We report a novel mouse model that conditionally expresses the most common human NPM1 mutation (type A) in the hematopoietic compartment.

View Article and Find Full Text PDF

Acute myeloid leukemia (AML) carrying nucleophosmin (NPM1) mutations displays distinct molecular and clinical-pathological features that led to its inclusion as provisional entity in 2008 WHO classification of myeloid neoplasms. Since NPM1 mutations behave as a founder genetic lesion in AML, they could be an attractive target for therapeutic intervention. Here, we discuss the potential for developing targeted therapies for NPM1-mutated AML with focus on: (i) interfering with the abnormal traffic of the NPM1 leukemic mutant, i.

View Article and Find Full Text PDF

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.

View Article and Find Full Text PDF

Human Papillomavirus type 77 is a skin type found in non-melanoma skin cancers of immuno-compromised individuals. Although, the HPV77 E6 oncoprotein has been well studied, nothing is known about E7. Studies on mucosal HPV types (e.

View Article and Find Full Text PDF