50 Because of

these unique features, NPM1-mutated AML has been included as provisional entity in the current WHO classification of myeloid neoplasms. 2 The role played by the NPM1 mutations in AML development is still partially understood. The normal NPM1 protein is involved in a variety of functions, including ribosome biogenesis, control of centrosome duplication and stabilization of ARF protein in the nucleoli. 51 More recent findings suggest that NPM1 may also play a role in regulating transcription 52 and apoptosis. 53 Whether mutations contribute to AML by interfering with one or more of these functions remains to be established. However, it is clear that the leukemogenic Androgen Receptor Antagonist effect of NPM1 mutants is strictly dependent on the perturbation of the traffic of nucleophosmin. Erlotinib 38 In fact, all mutations act finalistically to get the mutants into the cytoplasm. 54 A recently developed mice model has shown that mutant

Npm1 knock-in alleles are AML-initiating lesions causing Hox gene overexpression, increased self-renewal, and expanded myelopoiesis. 55 Cooperation of NPM1 mutants with other genetic lesions led to delayed-onset AML in about one-third of animals. 55NPM1 mutations frequently associate with mutations affecting the FLT3, DNMT3A and IDH1 genes that are likely to play a cooperative role in leukemogenesis. 14 Presenting clinical and laboratory features of NPM1-mutated AML usually include predominance of female sex, hypercellular marrow and high white blood cell

counts; the leukemic cells frequently show strong expression of CD33 but negativity for the CD34 antigen. 56NPM1-mutated AML exhibits high sensitivity toward induction chemotherapy that appears independent by the FLT3-ITD status. 57 Many studies have shown that NPM1 mutations without concomitant FLT3-ITD mutation are associated with a lower cumulative incidence of relapse leading to better leukemia-free survival and overall survival. [6], [41] and [58] These Methocarbamol effects have been mainly reported in the context of younger adults (< 60 years old) with CN-AML 14 but they seem to be operative also in the presence of an aberrant karyotype 47 or multilineage dysplasia. 48 The mechanism of the more favourable outcome of this genotype remains unclear. An appealing hypothesis is that this could be related to the immunogenicity of NPM1 mutants 59 that have been shown to induce specific CD4 + and CD8 + T cell responses. 60 After conventional chemotherapy, younger AML patients carrying an NPM1 mutation without FLT3-ITD show an overall survival of about 60% that is similar to that of core-binding factor (CBF) AML. [6] and [61] These data prompted to incorporate the genotype “mutated NPM1 without FLT3-ITD” (CN-AML only) into the genetic favorable-risk category.