Page 12 - 2019_07 resto del Mondo-web

Editorials
A
B
Figure 2. The dual role of NIPBL. (A) Zebrafish embryos were treated with nipblb-MO, an anti- sense oligonucleotide morpholino targeting the ATG region of nipblb. Twenty-four hours post-fer- tilization (hpf) there was a decrease in canonical Wnt pathway activation; however, at 48 hpf the pathway was hyperactivated, suggesting that nipblb plays a dual role in canonical Wnt path- way regulation. (B) When NIPBL is mutated in human germline embryonic tissue there is a decrease in canonical Wnt signaling, which leads to impaired neural development and pro- gression to Cornelia de Lange syndrome (CdLS). When NIPBL is downregulated in cooperation with NPMc+ mutation in somatic adult cells there is hyper-activation of the canonical Wnt signaling pathway, which leads to impaired myeloid differentiation and progression to acute myeloid leukemia (AML).
Cornelia de Lange syndrome, a rare developmental disorder with varying genomic landscapes and phenotypic expres- sion. NIPBL is the most commonly mutated gene in patients with Cornelia de Lange syndrome and, when its expression is low, confers the most severe phenotype.11 When nipblb is knocked down in zebrafish there is a significant downregu- lation of ccnd1, a direct target of the Wnt signaling path- way.12 CCND1 is also downregulated in almost half of Cornelia de Lange syndrome patients with mutated NIPBL. This suggests that the most severely affected patients have low expression of NIPBL and subsequently low Wnt signal- ing that likely contributes to the disease phenotype.12 This is in contrast to the increased Wnt signaling associated with NPMc+ adult AML. Cohesin mutations have been identi- fied in patients with AML although they are usually deter- mined to be secondary events that contribute to clonal expansion rather than acting as the driving oncogenic muta- tion.13 The data reported in this issue of Haematologica are intended to shed light on the cooperation between NIPBL and NPMc+ in adult AML.9
To understand the role of NIPBL downregulation in NPMc+ AML patients, Mazzola et al. used zebrafish to study the effects of these genetic alterations on hematopoi- etic stem cells and myeloid progenitors, cell populations that are increased in patients.5,9 Embryos injected with a nip-
patients.6 Subsequent injection of dkk1b mRNA, an inhibitor of the Wnt signaling pathway, rescues the increase of spi1 myeloid progenitor cells suggesting NPMc+ altered hematopoiesis is Wnt-dependent.7 The canonical Wnt/β- catenin signaling pathway has been shown to play a role in the development of AML. When constitutively active β- catenin is expressed in normal primary human CD34+ stem cells, the stem cells maintain high levels of CD34 expression and have impaired myelo-monocytic differentiation.8 Analysis of a cohort of AML patients in the study by Simon et al. revealed several samples with aberrant expression of LEF-1, a transcription factor in Wnt signaling, and constitu- tive expression of the Wnt family members Wnt-1 and Wnt-2b.8 These findings are consistent with a role for the Wnt signaling pathway in the development and progression of AML.
In this issue of Haematologica, Mazzola et al. report specific downregulation of NIPBL/nipblb in a cohort of adult patients with NPMc+ AML and in NPMc+ zebrafish embryos, respectively, and sought to understand the role of this cooperation in AML (Figure 1A).9 Wildtype NIPBL is a cohesin-loading factor essential to cohesin complex func- tion in the maintenance of the genome, specifically in repli- cating chromatids and DNA damage repair.10 NIPBL is one of five cohesin complex genes mutated in association with
1290
haematologica | 2019; 104(7)