NPM1 Biology in Myeloid Neoplasia

Flow cytometric immunophenotypic alterations of persistent clonal haematopoiesis in remission bone marrows of patients with NPM1‐mutated acute myeloid leukaemia

“…As expected for NPM1 mut AML, 82% of these neoplasms had a diploid karyotype and carried other co‐mutations. The frequency and distribution of these mutations is similar to what has been reported in NPM1 mut AML 23‐26,40 . Approximately half of the patients received intensive chemotherapy with or without venetoclax, and another half received hypomethylating agents (HMA) (27%) or low‐dose chemotherapy, either with venetoclax or other small molecule inhibitors.…”

“…To understand the potential clinical importance of these immunophenotypically aberrant cells, and examine their association with persistent CH, we conducted the present study on a cohort of patients with nucleophosmin 1‐mutated ( NPM1 mut ) AML. We chose this specific subtype of AML for the following reasons: i) NPM1 mutations occur in ∼30% of AML and co‐mutations in other genes including FMS‐like tyrosine kinase 3 ( FLT3 ), DNMT3A , IDH1, IDH2, and TET2 , are frequent 23–26 . Several of these mutations have been shown to persist beyond attaining NPM1 mut ‐negative remission 19 , 27,28 ; ii) NPM1 mutation is strongly associated with AML and is particularly rare in the CH setting 3,29 ; iii) NPM1 mut cells are highly sensitive to therapy and NPM1 mutation frequently becomes undetectable in patients who achieve a durable remission; and iv) Most NPM1 mut AML cases show highly aberrant and characteristic immunophenotypic alterations at diagnosis, being frequently negative for CD34, with an acute promyelocytic leukaemia (APL)‐like immunophenotype or monocytic differentiation 30 .…”

NPM1-Mutated Myeloid Neoplasms with <20% Blasts: A Really Distinct Clinico-Pathologic Entity?

“…Since the earliest observations, the rare finding of NPM1 mutations in MNs with <20% blasts in small and mainly retrospective series, has been commonly associated with an aggressive clinical course and relatively rapid progression to overt AML, usually within 12 months since diagnosis, as detailed in Table 3 [5,40,45,46,62,69,71,75]. However, most of these previous studies have interrogated for NPM1 mutations using limited single-gene PCR assays, without the possibility to compare the genetic profiles of NPM1-mutated MNs with the mutational landscape of most frequent MDS and MDS/MPN cases lacking NPM1 mutations [87,88]. Several studies examining large numbers of MDS and CMML samples by high-throughput sequencing technologies at diagnosis have identified more than 40-50 recurrently mutated genes, with greater than 80-90% of patients showing at least one somatic gene mutation (Table 4) [59,63,67,[89][90][91][92][93][94][95][96].…”

“…In summary, to the best of our knowledge, detailed information about therapeutic approaches in non-acute NPM1-mutated MNs are available for only 27 and 75 patients receiving intensive chemotherapy and HMA, respectively, as shown in Table 2. Due to the limited number of available data, mainly from retrospective studies lacking a controlled clinical trial design, no firm evidence-based conclusion can so far be drawn about the best treatment for NPM1-mutated MNs with <20% blasts [5,79,87,88]. Nevertheless, overall poor outcomes have been observed in most NPM1-mutated MNs patients, and upfront moderate intensity therapy, based on HMA, could be frequently considered inadequate.…”

Pulling the Pin on NPMc⁺ acute myeloid leukemia

“…The mutations, collectively termed NPMc + , cluster at the 3’ end of the NPM1 open reading frame and introduce a nuclear export signal that causes relocalization of nucleophosmin from the nucleolus to the cytoplasm. 2 Evidence from clinical trials had suggested that RA treatment may enhance the efficacy of intensive chemotherapy in a subset of NPMc + patients. 3 Excitingly, two concurrent studies in 2015 implicated RA as a degrader of mutant nucleophosmin, 4 , 5 but did not elucidate the molecular target of RA responsible for this effect.…”