H2020Индивидуална стипендия2019–2021

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

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2019-02-01 → 2021-01-31
Финансиране от ЕС: 168 277 €
Участници: 1
Схема: MSCA-IF-EF-SE

Линиите свързват координатора с партньорите.

Накратко на български

Връзката между тризомия 21 и мутации в гена GATA1 се анализира, за да се разбере произходът на специфични детски левкемии. Разкриването на тези механизми помага за по-доброто разбиране на развитието на рака при деца.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

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

Childhood leukaemias manifest in the first few years of life, which suggests an embryonic origin of the diseases and a possible contribution of haemopoietic progenitor cells generated during embryonic life in driving these types of cancers. In this context, the Down syndrome-associated transient myeloproliferative disorder (DS-TMD) is a paradigmatic example of perinatal malignancy, affecting around 10% of DS newborns. TMD is a pre-leukaemic condition characterized by the expansion of immature megakaryoblasts; although most cases resolve spontaneously, nearly 20% later progress to full-blown acute megakaryoblastic leukaemia (AMKL). Since both TMD and AMKL share the same somatic mutations in the transcription factor GATA1, AMKL is thought to derive from the first transient disease upon acquisition of additional mutations. Interestingly, the progression from TMD to AMKL occurs only within the first 4 years of life, suggesting an early developmental derivation of the pathology, which is yet to be precisely determined. Moreover, as GATA1 mutations in a disomic background do not cause leukaemia, there must be a strong interplay between GATA1 and trisomy 21, whose mechanisms are currently poorly understood. For this reason, unravelling the molecular bases of this interaction is paramount to the understanding of the disease. The overall goal of this proposal was to investigate the cellular origin and mechanisms of DS-TMD/AMKL. More generally, these findings could be applicable also to other types of childhood leukaemias. Research on cancer and childhood leukaemias is of broad interest for the EC, as shown by the extensive funding of projects on this topic. Hence, our project further nurtures this research area, contributing to increasing European research competitiveness.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

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.

Оригинален текст от CORDIS (на английски).

Участници

OSPEDALE SAN RAFFAELE SRL · MilanoКоординаторИталия