LEUKEYOLK | Uncovering the origin and mechanisms of Down syndrome-associated leukaemia through human induced pluripotent stem cell-derived haemopoiesis

Summary
This project aims at dissecting the contribution of yolk sac (YS)-derived haemopoietic progenitors to childhood leukaemias, whose early onset suggests an embryonic origin. Using induced pluripotent stem cell (iPSC) differentiation, we will determine the origin of the Down syndrome-associated transient myeloproliferative disease (DS-TMD), paradigmatic example of perinatal malignancy. TMD, due to megakaryoblast hyperproliferation, has an in utero origin. This supports the compelling hypothesis of a haemopoietic stem cell (HSC)-independent origin of DS-TMD, as during embryogenesis there are at least 3 waves of progenitors with megakaryocytic potential. A first primitive program, followed by the erythromyeloid progenitors (EMP), both YS-derived and devoid of HSC potential; lastly a definitive program, generating HSCs and all haemopoietic lineages. By differentiating iPSCs from a DS-TMD patient through recapitulation of embryonic development, we will interrogate the contribution of primitive, EMP and definitive haemopoiesis to DS-TMD with in vitro/in vivo functional assays. Moreover, we will investigate the molecular mechanisms triggering the disease. As mutations leading to a short GATA1 isoform occur in all cases of DS-TMD, we will analyse how this affects the transcriptional landscape of the cells relevant to the disease. We hypothesise that DS-TMD derives from a rarely appreciated developmental program (the EMP), whose life-long contribution is only beginning to be elucidated. Determining the developmental source and mechanisms of this disorder could help designing new therapies for myeloid malignancies in non-DS patients and could lead to a paradigm shift in the field of haemopoiesis and leukaemogenesis. Research on cancer and childhood leukemias is of broad interest for the EC, as shown by the extensive funding of projects on this topic within the FP7. Our project will further nurture this research area, contributing to increasing European research competitiveness.
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More information & hyperlinks
Web resources: https://cordis.europa.eu/project/id/796327
Start date: 01-02-2019
End date: 31-01-2021
Total budget - Public funding: 168 277,20 Euro - 168 277,00 Euro
Cordis data

Original description

This project aims at dissecting the contribution of yolk sac (YS)-derived haemopoietic progenitors to childhood leukaemias, whose early onset suggests an embryonic origin. Using induced pluripotent stem cell (iPSC) differentiation, we will determine the origin of the Down syndrome-associated transient myeloproliferative disease (DS-TMD), paradigmatic example of perinatal malignancy. TMD, due to megakaryoblast hyperproliferation, has an in utero origin. This supports the compelling hypothesis of a haemopoietic stem cell (HSC)-independent origin of DS-TMD, as during embryogenesis there are at least 3 waves of progenitors with megakaryocytic potential. A first primitive program, followed by the erythromyeloid progenitors (EMP), both YS-derived and devoid of HSC potential; lastly a definitive program, generating HSCs and all haemopoietic lineages. By differentiating iPSCs from a DS-TMD patient through recapitulation of embryonic development, we will interrogate the contribution of primitive, EMP and definitive haemopoiesis to DS-TMD with in vitro/in vivo functional assays. Moreover, we will investigate the molecular mechanisms triggering the disease. As mutations leading to a short GATA1 isoform occur in all cases of DS-TMD, we will analyse how this affects the transcriptional landscape of the cells relevant to the disease. We hypothesise that DS-TMD derives from a rarely appreciated developmental program (the EMP), whose life-long contribution is only beginning to be elucidated. Determining the developmental source and mechanisms of this disorder could help designing new therapies for myeloid malignancies in non-DS patients and could lead to a paradigm shift in the field of haemopoiesis and leukaemogenesis. Research on cancer and childhood leukemias is of broad interest for the EC, as shown by the extensive funding of projects on this topic within the FP7. Our project will further nurture this research area, contributing to increasing European research competitiveness.

Status

CLOSED

Call topic

MSCA-IF-2017

Update Date

28-04-2024
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Horizon 2020
H2020-EU.1. EXCELLENT SCIENCE
H2020-EU.1.3. EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions (MSCA)
H2020-EU.1.3.2. Nurturing excellence by means of cross-border and cross-sector mobility
H2020-MSCA-IF-2017
MSCA-IF-2017