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Roles of Homeoproteins in Lymphoid Organ Development

Periodic Report Summary 1 - HINLOD (Roles of homeoproteins in lymphoid organ development)

Developmental and cancer biology can be seen as two complementary disciplines. Whereas developmental biology is concerned with mechanisms underlying the acquisition and maintenance of normal cellular identity and function, cancer biology focuses on the disruption of such mechanisms and thus on abnormal cell function. Understanding what goes wrong when a cell becomes cancerous requires knowledge of the processes that ensure correct function of the same cell type during normal development. It is now clear that many oncogenes and tumour suppressors encode for transcription factors that are crucial in orchestrating developmental processes including organogenesis. To this end we set to identify and characterise novel molecular networks regulated by oncogenic transcription factors during organogenesis through the following specific objectives:

i) identification of the growth-related regulatory networks and target genes controlled by homeoproteins during organogenesis;
ii) validation of the in vivo expression and cellular localization of potential target genes;
iii) functional characterisation of candidate targets during organ growth.

Over the past two years we performed a comprehensive microarray analysis to identify genes regulated by a set of oncogenic transcription factors during organ development. In particular, we have performed a bioinformatic analysis and identified potential target genes of those transcription factors. We are currently validating target genes via RT-PCR and immunohistochemical analyses. To date, we have corroborated several potential targets and have uncovered developmental pathways controlled by those transcription factors. Among those, we found that some target pathways are associated with proliferation and differentiation of progenitor cells during organogenesis. Our final goal is to reach a comprehensive view of the genetic and transcription networks underlying organ development.

We foresee that the identification of oncogenic transcription factor target genes and developmental pathways during organogenesis will likely have implications for understanding the molecular mechanisms by which they induce cellular transformation and tumour progression.