TY - JOUR
T1 - Dysregulation of NIPBL leads to impaired RUNX1 expression and haematopoietic defects
AU - Mazzola, Mara
AU - Pezzotta, Alex
AU - Fazio, Grazia
AU - Rigamonti, Alessandra
AU - Bresciani, Erica
AU - Gaudenzi, Germano
AU - Pelleri, Maria Chiara
AU - Saitta, Claudia
AU - Ferrari, Luca
AU - Parma, Matteo
AU - Fumagalli, Monica
AU - Biondi, Andrea
AU - Cazzaniga, Giovanni
AU - Marozzi, Anna
AU - Pistocchi, Anna
N1 - Funding Information:
The work described in this paper was supported by Individual My first AIRC grant (MFAG #18714) and Piano di Sostegno alla Ricerca 2018 Linea 2, Dept. Biotecnologie Mediche e Medicina Traslazionale, Universit? degli Studi di Milano (PSR Linea2 2018) to AP, and AIRC grant IG-21999 to GC. The authors thank Carol Burns for the runx1 mRNA. They also thank Dorela Meta and Giulia Salmoiraghi for technical help in data preparation.
Publisher Copyright:
© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/6/1
Y1 - 2020/6/1
N2 - The transcription factor RUNX1, a pivotal regulator of HSCs and haematopoiesis, is a frequent target of chromosomal translocations, point mutations or altered gene/protein dosage. These modifications lead or contribute to the development of myelodysplasia, leukaemia or platelet disorders. A better understanding of how regulatory elements contribute to fine-tune the RUNX1 expression in haematopoietic tissues could improve our knowledge of the mechanisms responsible for normal haematopoiesis and malignancy insurgence. The cohesin RAD21 was reported to be a regulator of RUNX1 expression in the human myeloid HL60 cell line and during primitive haematopoiesis in zebrafish. In our study, we demonstrate that another cohesin, NIPBL, exerts positive regulation of RUNX1 in three different contexts in which RUNX1 displays important functions: in megakaryocytes derived from healthy donors, in bone marrow samples obtained from adult patients with acute myeloid leukaemia and during zebrafish haematopoiesis. In this model, we demonstrate that alterations in the zebrafish orthologue nipblb reduce runx1 expression with consequent defects in its erythroid and myeloid targets such as gata1a and spi1b in an opposite way to rad21. Thus, also in the absence of RUNX1 translocation or mutations, additional factors such as defects in the expression of NIPBL might induce haematological diseases.
AB - The transcription factor RUNX1, a pivotal regulator of HSCs and haematopoiesis, is a frequent target of chromosomal translocations, point mutations or altered gene/protein dosage. These modifications lead or contribute to the development of myelodysplasia, leukaemia or platelet disorders. A better understanding of how regulatory elements contribute to fine-tune the RUNX1 expression in haematopoietic tissues could improve our knowledge of the mechanisms responsible for normal haematopoiesis and malignancy insurgence. The cohesin RAD21 was reported to be a regulator of RUNX1 expression in the human myeloid HL60 cell line and during primitive haematopoiesis in zebrafish. In our study, we demonstrate that another cohesin, NIPBL, exerts positive regulation of RUNX1 in three different contexts in which RUNX1 displays important functions: in megakaryocytes derived from healthy donors, in bone marrow samples obtained from adult patients with acute myeloid leukaemia and during zebrafish haematopoiesis. In this model, we demonstrate that alterations in the zebrafish orthologue nipblb reduce runx1 expression with consequent defects in its erythroid and myeloid targets such as gata1a and spi1b in an opposite way to rad21. Thus, also in the absence of RUNX1 translocation or mutations, additional factors such as defects in the expression of NIPBL might induce haematological diseases.
KW - AML
KW - haematopoiesis
KW - NIPBL
KW - RUNX1
KW - zebrafish
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U2 - 10.1111/jcmm.15269
DO - 10.1111/jcmm.15269
M3 - Article
C2 - 32323916
AN - SCOPUS:85083767765
VL - 24
SP - 6272
EP - 6282
JO - Journal of Cellular and Molecular Medicine
JF - Journal of Cellular and Molecular Medicine
SN - 1582-1838
IS - 11
ER -