ZEBRAFISH AS A NOVEL MODEL TO STUDY GATA2 HAPLOINSUFFICIENCY SYNDROMES
Author(s): ,
Emanuele Gioacchino
Affiliations:
hematology,Erasmus MC,Rotterdam (NL),Netherlands
,
Cansu Koyunlar
Affiliations:
hematology,Erasmus MC,Rotterdam (NL),Netherlands
,
Hans de looper
Affiliations:
hematology,Erasmus MC,Rotterdam (NL),Netherlands
,
Joke Peulen
Affiliations:
hematology,Erasmus MC,Rotterdam (NL),Netherlands
,
Dennis Bosch
Affiliations:
hematology,Erasmus MC,Rotterdam (NL),Netherlands
,
Remco hoogenboezem
Affiliations:
hematology,Erasmus MC,Rotterdam (NL),Netherlands
,
paulette van strien
Affiliations:
hematology,Erasmus MC,Rotterdam (NL),Netherlands
,
Eric Bindels
Affiliations:
hematology,Erasmus MC,Rotterdam (NL),Netherlands
,
Ivo Touw
Affiliations:
hematology,Erasmus MC,Rotterdam (NL),Netherlands
Emma de Pater
Affiliations:
hematology,Erasmus MC,Rotterdam (NL),Netherlands
EHA Library. gioacchino E. Jun 14, 2019; 266146; PF346
Emanuele gioacchino
Emanuele gioacchino
Contributions
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Abstract

Abstract: PF346

Type: Poster Presentation

Presentation during EHA24: On Friday, June 14, 2019 from 17:30 - 19:00

Location: Poster area

Background
Patients with GATA2 mutations have up to 80% chance to develop a myeloid malignancy. MonoMAC and Emberger syndromes are GATA2 deficiency syndromes and are characterized by monocytopenia, B, NK cell lymphopenia and a predisposition to acute myeloid leukemia (AML). Although the disease initiating mutation is known, it is unclear how these patients develop hematological malignancies.

Aims
In our research we use both mouse and zebrafish models of Gata2 haploinsufficiency to describe their phenotypes and study the mechanisms of malignant transformation.

Methods
In mice we analyzed the transcriptome and functionality of LSK SLAM in Gata2 mutants. In zebrafish, two orthologues of Gata2 exist: gata2a and gata2b of which gata2b was shown to be predominantly expressed in hematopoietic cells. We used CRISPR-Cas9 to generate zebrafish gata2b mutants and evaluate their phenotype using flow cytometry, RNAseq, histology and in situ hybridization. Using single-cell RNA sequencing we aim to identify early onset markers of dysplasia and unveil the mechanism of malignant transformation.

Results
Gata2 heterozygous mutant mice survive into adulthood without developing signs of alterations in the myeloid lineage. Phenotypic HSCs of these mutant adult mice have unchanged Gata2 expression but are lower in frequency, more proliferative and transcriptionally more committed to differentiation compared to WT. Additionally, they display increased DNA damage indicating these HSCs experience proliferative stress. gata2b+/- zebrafish show reduced myeloid differentiation and the kidney marrow smears of this aged fish show dysplastic myeloid cells.

Conclusion
Our mouse model doesn’t incur a malignancy even though it acquires an HSCs phenotype. Our zebrafish model develops a dysplastic kidney marrow and recapitulates characteristics of the GATA2 deficiency syndromes. Both models can give new insights into the physiopathology of these diseases.

 

Session topic: 11. Bone marrow failure syndromes incl. PNH - Biology & Translational Research

Keyword(s): MDS/AML, Zebra fish

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