THE ROLE OF GATA2 IN HSC GENERATION THROUGH ENDOTHELIAL-TO-HEMATOPOIETIC TRANSITION.
Author(s): ,
Cansu Koyunlar
Affiliations:
Hematology,Erasmus Medical Center,Rotterdam,Netherlands
,
Emanuele Gioacchino
Affiliations:
Hematology,Erasmus Medical Center,Rotterdam,Netherlands
,
Remco Hoogenboezem
Affiliations:
Hematology,Erasmus Medical Center,Rotterdam,Netherlands
,
Hans de Looper
Affiliations:
Hematology,Erasmus Medical Center,Rotterdam,Netherlands
,
Dennis Bosch
Affiliations:
Hematology,Erasmus Medical Center,Rotterdam,Netherlands
,
Jonathan Klavert
Affiliations:
Hematology,Erasmus Medical Center,Rotterdam,Netherlands
,
Marije Havermans
Affiliations:
Hematology,Erasmus Medical Center,Rotterdam,Netherlands
,
Paulette van Strien
Affiliations:
Hematology,Erasmus Medical Center,Rotterdam,Netherlands
,
Eric Bindels
Affiliations:
Hematology,Erasmus Medical Center,Rotterdam,Netherlands
,
Ruud Delwel
Affiliations:
Hematology,Erasmus Medical Center,Rotterdam,Netherlands
,
Elaine Dzierzak
Affiliations:
Cell Biology,Erasmus Medical Center,Rotterdam,Netherlands;The Queen's Medical Research Institute College of Medicine and Veterinary Medicine,Edinburgh,United Kingdom
,
Ivo Touw
Affiliations:
Hematology,Erasmus Medical Center,Rotterdam,Netherlands
Emma de Pater
Affiliations:
Hematology,Erasmus Medical Center,Rotterdam,Netherlands
EHA Library. Koyunlar C. Jun 15, 2019; 267445; S862
Cansu Koyunlar
Cansu Koyunlar
Contributions
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Abstract

Abstract: S862

Type: Oral Presentation

Presentation during EHA24: On Saturday, June 15, 2019 from 11:45 - 12:00

Location: Hall E106

Background
GATA2 is the most frequently mutated gene in childhood AML. These patients have germline mutations in one allele of GATA2 and have a high predisposition for MDS/AML. Also, in mouse, Gata2 is required for embryonic HSC generation and survival and complete deletion of Gata2 is lethal at embryonic day (E)10, while Gata2 haploinsufficiency results in a severe reduction in the formation of HSCs. The first HSCs are formed at E10.5 through a process called endothelial-to-hematopoietic transition (EHT) from specialized hemogenic endothelial cells of the dorsal aorta in the aorta-gonad-mesonephros (AGM) region.

Aims
As all patients suffering from GATA2 haploinsufficiency syndromes have innate GATA2 mutations, our hypothesis is that embryonic haploinsufficiency of GATA2 is responsible for the phenotype of the patients. Therefore, we want to understand how Gata2 haploinsufficiency affects the generation of HSCs through EHT.

Methods
We sorted phenotypic HSPCs (CD31+cKit+ cells) from WT and Gata2+/- E11 AGMs and performed transcriptome analysis. Also, with whole-mount antibody staining performed on the WT and Gata2+/- AGMs, we analysed CD31+cKit+ cell populations.

Results
Surprisingly, we found that the hematopoietic transcriptional program is not abrogated in Gata2+/- mouse E11 CD31+cKit+ cells. However, Gata2+/- HSPCs still express the endothelial program indicating that the hematopoietic cells are stuck in the endothelium and cannot complete EHT. We found that Gfi1b is downregulated in Gata2+/- HSPCs. As Gfi1b is known to be required for downregulation of the endothelial program for EHT during primitive hematopoiesis, we hypothesize that Gata2 directly regulates Gfi1b and that this regulation is required for normal EHT.

Conclusion
In conclusion, we showed Gata2+/- HSPCs are transcriptionally different from WT HSPCs. We are currently studying if a specific HSPC subtype can overcome Gata2 haploinsufficiency and will still undergo EHT as this may have implications for the hematopoietic cells that eventually populate the hematopoietic tissues.

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

Keyword(s): GATA-2, MDS/AML

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