PUBLICATION

NIPBL: a new player in myeloid cells differentiation

Authors

Mazzola, M., Deflorian, G., Pezzotta, A., Ferrari, L., Fazio, G., Bresciani, E., Saitta, C., Ferrari, L., Fumagalli, M., Parma, M., Marasca, F., Bodega, B., Riva, P., Cotelli, F., Biondi, A., Marozzi, A., Cazzaniga, G., Pistocchi, A.

ID

ZDB-PUB-190113-12

Date

2019

Source

Haematologica 104(7): 1332-1341 (Journal)

Registered Authors

Bresciani, Erica, Cotelli, Franco, Deflorian, Gianluca

Keywords

Acute Myeloid Leukemia, Hematopoietic Stem Cell, NIPBL, NPMc+, zebrafish

MeSH Terms

Cell Differentiation*
Humans
Leukemia, Myeloid, Acute/genetics
Leukemia, Myeloid, Acute/metabolism
Leukemia, Myeloid, Acute/pathology*
Mutation*
Wnt Signaling Pathway
Embryo, Nonmammalian/metabolism
Embryo, Nonmammalian/pathology
Zebrafish
Adult
Chromosomal Proteins, Non-Histone/genetics
Chromosomal Proteins, Non-Histone/metabolism*
Nuclear Proteins/genetics*
Animals
Cell Cycle Proteins/genetics
Cell Cycle Proteins/metabolism*
Hematopoiesis
Phenotype
Gene Expression Regulation, Neoplastic*

(all 20)

PubMed

30630974 Full text @ Haematologica

Abstract

NUCLEOPHOSMIN1 (NPM1) is the most frequently mutated gene in acute myeloid leukemia. Notably, NPM1 mutations are always accompanied by additional mutations such as those in cohesin genes RAD21, SMC1A, SMC3, STAG2 but not in the cohesin regulator NIPBL. In this work, we analyze a cohort of adult patients with acute myeloid leukemia and NPM1 mutation and we observe specific reduction in the expression of NIPBL but not in other cohesin genes. In our zebrafish model, the overexpression of the mutated form of NPM1 also induced the down-regulation of nipblb, the zebrafish orthologue of the human NIPBL. To investigate the hematopoietic phenotype and the interaction between mutated NPM1 and nipblb, we generate a zebrafish model with nipblb down-regulation that shows an increased number of myeloid progenitors. This phenotype is due to a hyper activation of the canonical Wnt pathway: the rescue of myeloid cells blocked in an undifferentiated state is possible when the Wnt pathway is inhibited by ddk1b mRNA injection or indomethacin administration. Our results reveal for the first time a role for NIPBL during zebrafish hematopoiesis and suggest that NIPBL/NPM1 interplay may regulate myeloid differentiation in zebrafish and humans through the canonical Wnt pathway and that dysregulation of these interactions may drive to leukemic transformations.

Genes / Markers

Figures

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Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
axin2	AB + MO3-nipblb	control	Protruding-mouth	whole organism	RTPCR	Fig. 3
GFP	w25Tg + MO3-nipblb	control	Protruding-mouth	caudal hematopoietic tissue	IFL	Fig. 3
spi1b	AB + MO3-nipblb	control	Protruding-mouth	caudal hematopoietic tissue	ISH	Fig. 5
spi1b	AB + MO3-nipblb	chemical treatment by environment: indometacin	Protruding-mouth	caudal hematopoietic tissue	ISH	Fig. 5

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
AB + MO3-nipblb	control	Protruding-mouth	caudal hematopoietic tissue spi1b expression increased amount, abnormal	Fig. 5
AB + MO3-nipblb	control	Protruding-mouth	caudal hematopoietic tissue common myeloid progenitor increased amount, abnormal	Fig. 5
AB + MO3-nipblb	control	Protruding-mouth	caudal hematopoietic tissue common myeloid progenitor increased amount, abnormal	Fig. 2
AB + MO3-nipblb	control	Protruding-mouth	whole organism axin2 expression increased amount, abnormal	Fig. 3
AB + MO3-nipblb	control	Day 4	caudal hematopoietic tissue neutrophil decreased amount, abnormal	Fig. 2
AB + MO3-nipblb	chemical treatment by environment: indometacin	Protruding-mouth	caudal hematopoietic tissue spi1b expression amount, ameliorated	Fig. 5
AB + MO3-nipblb	chemical treatment by environment: indometacin	Protruding-mouth	caudal hematopoietic tissue common myeloid progenitor amount, ameliorated	Fig. 5
la2Tg + MO3-nipblb	control	Protruding-mouth	caudal hematopoietic tissue common myeloid progenitor increased amount, abnormal	Fig. 2
la2Tg + MO3-nipblb	control	Protruding-mouth	hematopoietic stem cell canonical Wnt signaling pathway increased occurrence, abnormal	Fig. 4
w25Tg + MO3-nipblb	control	Protruding-mouth	caudal hematopoietic tissue canonical Wnt signaling pathway increased occurrence, abnormal	Fig. 3

1 - 10 of 11

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Mutations / Transgenics

Allele	Construct	Type
la2Tg	Tg(-6.0itga2b:EGFP)	Transgenic Insertion
s916Tg	Tg(kdrl:Hsa.HRAS-mCherry)	Transgenic Insertion
w25Tg	Tg(top:GFP)	Transgenic Insertion

1 - 3 of 3

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Human Disease / Model

Human Disease	Fish	Conditions	Evidence
acute myeloid leukemia			TAS

Sequence Targeting Reagents

Target	Reagent	Reagent Type
nipblb	MO2-nipblb	MRPHLNO
nipblb	MO3-nipblb	MRPHLNO

Fish

Fish
AB + MO3-nipblb
la2Tg + MO3-nipblb
w25Tg + MO3-nipblb

Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
EGFP	EFG	EGFP
GFP	EFG	GFP
mCherry	EFG	mCherry

Mapping

Mazzola et al., 2019 ZDB-PUB-190113-12 PMID:30630974

NIPBL: a new player in myeloid cells differentiation

Mazzola et al., 2019

ZDB-PUB-190113-12
PMID:30630974