Grant: Travel Awards - Institute Community Support

Lymphoid leukemia represents about 30% of childhood cancer cases. It is often caused by chromosomal rearrangements involving genes coding for transcription factors, controlling complex genetic programs that dictate which genes will be expressed. As an example, the oncogenic transcription factor LMO2 (LIM-only 2) is often aberrantly expressed in T cell acute lymphoblastic leukemia (T-ALL). In normal hematopoiesis, LMO2 is essential for the generation of hematopoietic stem cells that give rise to all blood cells. Moreover, some leukemic cells possess properties normally reserved to hematopoietic stem cells. Thus, studying the role of LMO2 in hematopoietic stem cells could be relevant to the contexts of normal hematopoiesis and leukemogenesis. To reveal new molecular functions for LMO2, I chose to identify its associated proteins. Unexpectedly, I identified interactions between LMO2 and proteins that are essential for DNA replication. The process of cell division, or cell cycle, is subdivided in four different phases: G1 (growth), S (DNA replication), G2 (growth) and M (mitosis, when the cell actually divides). During the S phase, the DNA of the mother cell is replicated in order to generate two daughter cells containing the exact same genetic material. This process is tightly regulated in all cell types. We demonstrated that LMO2 controls S phase progression in hematopoietic cells. When we reduce LMO2 levels in hematopoietic cells, we observe a delay in S phase progression. Conversely, when LMO2 is ectopically expressed in the T lymphocyte lineage, we observe an increase in DNA replication that precedes leukemia development. To our knowledge, this is the first evidence of a non-transcriptional function of the LMO2 oncogene. That could serve as a paradigm for other oncogenic transcription factors, particularly for other members of the LMO family that are all potent oncogenes.