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Editorials
blb antisense oligonucleotide morpholino (nipblb-MO) showed an increase in spi1b myeloid progenitors but did not show an increase in hematopoietic stem cells. However, when embryos were injected with NPMc+, there was an increase in both spi1b myeloid progenitors and cmyb hematopoietic stem cells, which suggests nipblb downregu- lation cooperates with NPMc+ as a secondary driver of impaired myeloid differentiation (Figure 1C).13 To further elucidate the relationship between NIPBL downregulation and NPMc+, Mazzola et al. focused on the downstream pathway these genes have in common: canonical Wnt/β- catenin signaling. They found that this pathway was hyper- activated in NPMc+ embryos and in embryos with nipblb- MO at 48 hours post fertilization (hpf) (Figure 1B). A dose- response assay demonstrated that subcritical doses of nip- blb-MO or NPMc+ given individually did not increase Wnt activation but co-injection of subcritical doses of nipblb-MO and NPMc+ did, which supports the hypothesis that nipblb and NPMc+ cooperate to drive hyper-activation of the canonical Wnt/β-catenin signaling pathway. Treatment with indomethacin, a pharmacological inhibitor of Wnt, rescued the increased hematopoietic stem cell and myeloid progenitor phenotype in nipblb-MO and NPMc+ embryos, thus confirming that hyper-activation of the Wnt signaling pathway contributes to impaired myeloid cell differentia- tion, an observation also made in AML patients (Figure 1D).8,9,14 The authors suggest that Wnt/β-catenin inhibitors, such as indomethacin, may be an applicable new therapeu- tic approach to treating NPMc+ AML patients. It is impor- tant to note that canonical Wnt pathway activation in NPMc+ AML patients in the cohort studied here was not significantly increased in patients with decreased NIPBL expression compared to the activation in those with normal or increased NIPBL expression. Larger cohorts and exten- sive Wnt pathway activation tests will be necessary before a clinical recommendation of indomethacin treatment can be made.
The study published by Mazzola et al. in this issue of Haematologica demonstrated that nipblb downregulation in zebrafish embryos induced Wnt pathway hyper-activation at 48 hpf. Interestingly, a previous study by the authors of this publication showed that at 24 hpf nipblb downregula- tion actually decreased Wnt pathway activation (Figure 2A).12 Taken together, these studies propose two roles for NIPBL in the regulation of canonical Wnt signaling. In one situation, early downregulation of NIPBL in germline embryonic tissue initiates impaired neural development due to decreased Wnt pathway activation, which leads to the clinical presentation of Cornelia de Lange syndrome.
Conversely, downregulation of NIPBL as a secondary event to NPMc+ confers hyper-activation of the Wnt pathway in hematopoietic stem cells and early myeloid progenitors which impairs normal hematopoietic differentiation and induces progression to AML (Figure 2B).9,15 The report in this issue of Haematologica tells a new tale of NIPBL and its cooperation with NPM1 in AML, thereby leading us to a greater understanding of the underlying molecular network that contributes to the disease.
References
1. Kouchkovsky ID, Abdul-Hay M. Acute myeloid leukemia: a compre- hensive review and 2016 update. Blood Cancer J. 2016;6(7):e441.
2. DombretH,GardinC.Anupdateofcurrenttreatmentsforadultacute myeloid leukemia. Blood. 2016;127(1):53-61.
3. RauR,BrownP.Nucleophosmin(NPM1)mutationsinadultandchild- hood acute myeloid leukemia: towards definition of a new leukemia entity. Hematol Oncol. 2009;27(4):171-181.
4. Falini B, Mecucci C, Tiacci E, et al. Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med. 2005;352(3):254-266.
5. Falini B, Nicoletti I, Martelli M, Mecucci C. Acute myeloid leukemia carrying cytoplasmic/mutated nucleophosmin (NPMc+ AML): biologic and clinical features. Blood. 2007;109(3):874-885.
6. Bolli N, Payne E, Grabher C. Expression of the cytoplasmic NPM1 mutant (NPMc+) causes the expansion of hematopoietic cells in zebrafish. Blood. 2010;115(16):3329-3340.
7. Barbieri E, Deflorian G, Pezzimenti F. Nucleophosmin leukemogenic mutant activates Wnt signaling during zebrafish development. Oncotarget. 2016;7(34):55302-55312.
8. Simon M, Grandage V, Linch D, Khwaja A. Constitutive activation of the Wnt/β-catenin signaling pathway in acute leukemia. Oncogene. 2005;24(14):2410-2420.
9. Mazzola M, Deflorian G, Pezzotta A, et al. NIPBL: a new player in myeloid cell differentiation. Haematologica. 2019;104(7):1332-1341
10. GaoD,ZhuB,CaoX,etal.RolesofNIPBLinmaintenanceofgenome stability. Semin Cell Dev Biol. 2018;S1084-9521(18):30162-30169.
11. Kaur M, Mehta D, Noon SE, et al. NIPBL expression levels in CdLS
probands as a predictor of mutation type and phenotypic severity. Am
J Med Genet C Semin Med Genet. 2016;172(2):163-170.
12. Pistocchi A, Fazio G, Cereda A, et al. Cornelia de Lange syndrome: NIPBL haploinsufficiency downregulates canonical Wnt pathway in zebrafish embryos and patients fibroblasts. Cell Death Dis.
2013;4(10):e866.
13. ThotaS,VinyA,MakishimaH,etal.Geneticalterationsofthecohesin
complex genes in myeloid malignancies. Blood. 2014;124(11):1790-
1798.
14. North T, Goessling W, Walkley C, et al. Prostaglandin E2 regulates ver-
tebrate hematopoietic stem cell homeostasis. Nature. 2007;447(7147):
1007-1011.
15. TholF,BollinR,GehlhaarM,etal.Mutationsinthecohesincomplex
in acute myeloid leukemia: clinical and prognostic implications. Blood. 2014;123(6):914-920.
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