LEUKAEMOGENESIS

Developmental Impact of MLL-AF4 Fusion Gene linked to Infant Acute Lymphoblastic Leukaemia on Human Stem Cell Fate

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 Obiettivo del progetto (Objective)

'The MLL gene is located in chromosome 11q23 and is implicated in >40 different chromosomal translocations, generating distinct leukaemic fusion genes. Unlike other MLL fusion proteins, t(4;11) MLL-AF4 is always found in infant pro-B-ALL with a dismal prognosis in infants and adults. In infant ALL where t(4;11) MLL-AF4 is very common (>80%), the gene fusion arises in utero. However, very little is known about the nature of the target cell for transformation in the embryo/foetus and the mechanisms accounting for its B-cell lineage affiliation. Haematopoietic stem (HSC) and progenitor (HPC) cells represent likely targets for transformation. However, mouse models and transformed cell lines have been used with only modest success to model the effects of MLL-AF4 and the disease phenotypes achieved do not faithfully mimic those seen in the actual infant disease. Moreover, MLL-AF4 protein seems toxic when retrovirally over-expressed in mouse or human stem cells. Here, we propose to explore the developmental impact of MLL-AF4 on human haematopoietic stem cell fate through consideration of distinct ontogeny (embryonic and cord blood-CB-) and hierarchical (HSCs and HPCs) stages of development. Based on state-of-the-art lentiviral and TAT-protein transduction technology, MLL-AF4 will be delivered into human cells in distinct ontogenic and hierarchical positions including: hESCs, CB-HSC and CB-HPCs. The potential transformation effects of MLL-AF4 will be assayed in vitro and in vivo by its ability to disrupt the balance between self-renewal and differentiation. These novel studies will provide insights into the developmental impact of MLL-AF4 on human stem cell transformation and fate, improving our understanding of the molecular pathogenesis and aetiology of this leukaemia. Finally, to study this complex genetic infant leukaemia it would be desirable to follow the development of cells carrying the disease mutation in the "dish" and see at which point the cells' function fails'

Introduzione (Teaser)

Leukaemia arises as a result of genetic or epigenetic alterations in blood cells, leading to an aberrant accumulation of undifferentiated blasts. Understanding the molecular pathogenesis and aetiology of infant leukaemia induced by the MLL-AF4 fusion gene was the subject of the Leukaemogenesis project.