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A tale of two genes: a new connection between NIPBL and NPM1 in acute myeloid leukemia Elizabeth A. R. Garfinkle1,2 and Tanja A. Gruber1
1Department of Oncology, St. Jude Children’s Research Hospital, Memphis TN and 2Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis TN, USA
E-mail: TANJA A. GRUBER - tanja.gruber@stjude.org doi:10.3324/haematol.2019.218867
Acute myeloid leukemia (AML), the most common acute leukemia in adults, is defined by few somatic mutations in myeloid stem cells which drive abnormal prolifera- tion and inhibit normal differentiation.1 The overall survival rate of adults with AML remains low despite current front-line induction therapy using cytarabine and an anthracycline fol- lowed by a hematopoietic stem cell transplant in first remis- sion for high-risk patients.2 Defining the molecular mecha- nisms by which AML-associated somatic mutations drive leukemogenesis will illuminate new key pathways for thera- peutic intervention to improve patient outcomes.
One of the most frequently mutated genes in adult AML is nucleophosmin (NPM1) which encodes a chaperone protein
crucial to genomic stability, protein synthesis, and cell cycle regulation. Wildtype NPM1 localizes primarily to the nucleo- lus, but has the ability to shuttle rapidly between the nucleus and the cytoplasm.3 About one third of primary adult AML cases with a normal karyotype harbor an oncogenic NPM1 mutation, often in the C-terminal nuclear export signal (NES) that causes aberrant cytoplasmic translocation (NPMc+) and subsequent disruption of normal cellular regulation.4,5 In zebrafish, a powerful model system for hematopoiesis, NPMc+ mRNA injection into embryos results in cytoplasmic expression and an increase in both cmyb positive definitive hematopoietic stem cells and spi1 positive myeloid progenitor cells, consistent with the phenotype of NPMc+ adult AML
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Figure 1. Model of leukemogenesis. (A) NIPBL/nipblb is downregulated in adult humans with acute myeloid leukemia (AML) and zebrafish embryos, respectively, harboring the NPMc+ mutation. (B) NPMc+ and nipblb downregulation drives hyper-activation of the canonical Wnt pathway. (C) Hyper-activation of the canonical Wnt pathway leads to an accumulation of cmyb hematopoietic stem cells (HSC) and spi1b myeloid progenitors. (D) The phenotype is res- cued upon treatment with the Wnt pharmacolog- ical inhibitor indomethacin, a possible new approach to the treatment of NPMc+ AML.
haematologica | 2019; 104(7)
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