Dactinomycin induces complete remission associated with nucleolar stress response in relapsed/refractory NPM1-mutated AML

Acute myeloid leukemia (AML) with mutated NPM1 accounts for one-third of newly diagnosed AML. Despite recent advances, treatment of relapsed/refractory NPM1-mutated AML remains challenging, with the majority of patients eventually dying due to disease progression. Moreover, the prognosis is particularly poor in elderly and unfit patients, mainly because they cannot receive intensive treatment. Therefore, alternative treatment strategies are needed. Dactinomycin is a low-cost chemotherapeutic agent, which has been anecdotally reported to induce remission in NPM1-mutated patients, although its mechanism of action remains unclear. Here, we describe the results of a single-center phase 2 pilot study investigating the safety and efficacy of single-agent dactinomycin in relapsed/refractory NPM1-mutated adult AML patients, demonstrating that this drug can induce complete responses and is relatively well tolerated. We also provide evidence that the activity of dactinomycin associates with nucleolar stress both in vitro and in vivo in patients. Finally, we show that low-dose dactinomycin generates more efficient stress response in cells expressing NPM1 mutant compared to wild-type cells, suggesting that NPM1-mutated AML may be more sensitive to nucleolar stress. In conclusion, we establish that dactinomycin is a potential therapeutic alternative in relapsed/refractory NPM1-mutated AML that deserves further investigation in larger clinical studies

A new genetic lesion in B-CLL: a NOTCH1 PEST domain mutation

[No abstract available

NOTCH1 PEST domain mutation is an adverse prognostic factor in B-CLL

[No abstract available

NOVEL NPM1 EXON 5 MUTATIONS AND GENE FUSIONS LEADING TO ABERRANT CYTOPLASMIC NUCLEOPHOSMIN IN AML

none32siNucleophosmin (NPM1) mutations in acute myeloid leukemia (AML) affect exon 12, but sporadically also exon 9 and 11, all causing changes at protein C-terminal end (loss of tryptophans and creation of a nuclear export signal-NES motif) that lead to aberrant cytoplasmic NPM1 (NPM1c+), detectable by immunohistochemistry. Combining immunohistochemistry and molecular analyses in 929 AML patients, we found non-exon 12 NPM1 mutations in 5/387 (1.3%) NPM1c+ cases. Besides mutations in exon 9 (n=1) and exon 11 (n=1), novel mutations in exon 5 were discovered (n=3). One more exon 5 mutation was identified in additional 141 AML patients selected for wild-type NPM1 exon 12. Furthermore, 3 NPM1 rearrangements (i.e. NPM1/RPP30, NPM1/SETBP1, NPM1/CCDC28A) were detected and characterized among 13,979 AML samples screened by cytogenetic/FISH and RNA sequencing. Functional studies demonstrated that in AML cases the new NPM1 proteins harboured an efficient extra NES, either newly created or already present in the fusion partner, ensuring its cytoplasmic accumulation. Our findings support NPM1 cytoplasmic relocation as critical for leukemogenesis and reinforce the role of immunohistochemistry in predicting any AML-associated NPM1 genetic lesions. Also, this study highlights the need for developing new specific assays for molecular diagnosis and monitoring of NPM1-mutated AML.noneMartelli, Maria Paola; Rossi, Roberta; Venanzi, Alessandra; Meggendorfer, Manja; Perriello, Vincenzo Maria; Martino, Giovanni; Spinelli, Orietta; Ciurnelli, Raffaella; Varasano, Emanuela; Brunetti, Lorenzo; Ascani, Stefano; Quadalti, Corinne; Cardinali, Valeria; Mezzasoma, Federica; Gionfriddo, Ilaria; Milano, Francesca; Pacini, Roberta; Tabarrini, Alessia; Bigerna, Barbara; Albano, Francesco; Specchia, Giorgina; Vetro, Calogero; Di Raimondo, Francesco; Annibali, Ombretta; Avvisati, Giuseppe; Rambaldi, Alessandro; Falzetti, Franca; Tiacci, Enrico; Sportoletti, Paolo; Haferlach, Torsten; Haferlach, Claudia; Falini, BrunangeloMartelli, Maria Paola; Rossi, Roberta; Venanzi, Alessandra; Meggendorfer, Manja; Perriello, Vincenzo Maria; Martino, Giovanni; Spinelli, Orietta; Ciurnelli, Raffaella; Varasano, Emanuela; Brunetti, Lorenzo; Ascani, Stefano; Quadalti, Corinne; Cardinali, Valeria; Mezzasoma, Federica; Gionfriddo, Ilaria; Milano, Francesca; Pacini, Roberta; Tabarrini, Alessia; Bigerna, Barbara; Albano, Francesco; Specchia, Giorgina; Vetro, Calogero; Di Raimondo, Francesco; Annibali, Ombretta; Avvisati, Giuseppe; Rambaldi, Alessandro; Falzetti, Franca; Tiacci, Enrico; Sportoletti, Paolo; Haferlach, Torsten; Haferlach, Claudia; Falini, Brunangel