Current status and future perspectives in targeted therapy of NPM1-mutated AML

Abstract

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. Starting from the structure and functions of NPM1, we provide an overview of the potential targeted therapies against NPM1-mutated AML and discuss strategies aimed at interfering with the oligomerization (compound NSC348884) and the abnormal traffic of NPM1 (avrainvillamide, XPO1 inhibitors) as well as at inducing selective NPM1-mutant protein degradation (ATRA/ATO, deguelin, (-)-epigallocatechin-3-gallate, imidazoquinoxaline derivatives) and at targeting the integrity of nucleolar structure (actinomycin D). We also discuss the current therapeutic results obtained in NPM1-mutated AML with the BCL-2 inhibitor venetoclax and the preliminary clinical results using menin inhibitors targeting HOX/MEIS1 expression. Finally, we review various immunotherapeutic approaches in NPM1-mutated AML, including immune check-point inhibitors, CAR and TCR T-cell-based therapies against neoantigens created by the NPM1 mutations.

Causal linkage of presence of mutant NPM1 to efficacy of novel therapeutic agents against AML cells with mutant NPM1

“…Recent reports have highlighted the promising preclinical and clinical anti-AML efficacy of other novel agents and their combinations in AML expressing NPM1c [28]. These include novel exportin-1 inhibitors [50,51], the nucleolar stress-inducing agent dactinomycin [52], the NPM1c protein-degrader arsenic trioxide and ATRA combination [28,53], and the BH3 mimetic venetoclax based combinations [54]. Immunotherapy of AML expressing mtNPM1 with anti-CD33 or CD123 strategies [55][56][57], anti-PD1 or PD-L1 antibodies-based combinations [58,59], or anti-CD123 directed chimeric antigen receptor (CAR-T) cells are also being investigated [60].…”

Prolonged XPO1 inhibition is essential for optimal antileukemic activity in NPM1-mutated AML

“…Although specific targeting of NPM1c has been so far revealed challenging 2,18 , venetoclax-based regimens and Menin-MLL inhibitors have recently proven effective in NPM1-mutated AML [19][20][21][22][23] . Therefore, there is growing interest in developing new targeted therapies for this entity 24 .…”

“… 20 , 21 , 22 , 23 , 24 Therefore, there is growing interest in developing new targeted therapies for this entity. 25 …”

Targeting and Monitoring Acute Myeloid Leukaemia with Nucleophosmin-1 (NPM1) Mutation

“…Since NPM1 proteins interact with a shuttling receptor XPO1, also known as Exportin, the mutant protein is exported at rates exceeding that at which it is imported, ultimately leading to the delocalisation of mutant NPM1 to the cytoplasm [ 3 ]. Wild type (WT) NPM1 is also shuttled out of the nucleus in the process, as NPM1-mutant and NPM1-WT form heterodimers to be co-exported [ 8 ].…”