Pathogenesis of T-cell Acute Lymphoblastic Leukemia from Myeloproliferative Disorder

T cell acute lymphoblastic leukemia (T-ALL) is a major type of pediatric leukemia.  T-ALL is generally thought to be developed from thymocytes.  However, recent studies from our lab suggest that T-ALL could be derived from cells of myeloid origin.  We recently developed an experimental model of myeloproliferative disorder (MPD) characterized as neoplasitc expansion of myeloid cells.  This MPD occurs in the mice injected with hematopoietic progenitors with a constitutively activated from of MEK (active MEK) that leads to activation of the MEK/ERK pathway.  Similar MPD is developed from hematopoietic progenitors with active MEK and Bcl-2, an anti-apopotic protein.  Notably, T-ALL occurs in 100% of mice injected with these Bcl-2/active MEK+ MPD cells in secondary transplants.  Since T-ALL developed in our experimental system show high Notch activity, we hypothesize that lineage conversion of myeloid progenitors to T cell lineage might occur in the presence of a constitutive activation form of Notch, ICN (Intracellular Notch).  This hypothesis is supported by previous findings that hematopoietic progenitors introduced with ICN can give rise to T-ALL.  We previously reported that lineage conversion from lymphoid to myeloid lineage can occur in lymphoid progenitors, but rarely from myeloid to lymphoid lineage.  Using this newly established experimental system, we aim to elucidate mechanisms of this lineage conversion, as well as to identify potential target molecules for the treatment of T-ALL.  The results of this project will give us new insights into the pathogenesis of T-ALL, which will have important impact in the clinical and basic science community.