Project summary
Mixed phenotype acute leukemia (MPAL) is a rare and aggressive leukemia with features of both acute myeloid
leukemia (AML) and acute lymphoblastic leukemia (ALL). MPAL patients are treated with either AML or ALL
regimens, and patient survival is significantly impacted by age. While the median survival of children with MPAL
is about 139 months, the median survival of the adult patients is only 11 months. Large scale integrative genomic
analyses of pediatric and adult MPAL have identified numerous genetic mutations. However, many mutations
are commonly seen in both adult and pediatric MPAL, suggesting that additional unidentified factors other than
genetic mutations may contribute to the poorer prognosis observed in adult patients with MPAL. Introduction of
MPAL genetic mutations in mouse models rarely leads to MPAL, instead typically results in AML or ALL. As a
result, it is difficult to study MPAL in vivo and understand how aging contributes to this disease. Recently, we
have developed an innovative mouse model of MPAL after serial bone marrow transplantation, in which about
90% mice developed spontaneous B/myeloid MPAL, a major subtype of human MPAL. MPAL in our model is
highly dependent on aging of bone marrow cells, as transplantation with young mouse bone marrow cells did
not result in such a phenotype. Strikingly, we found that gene knockout of histone deacetylase Sirt1 substantially
inhibited development of MPAL in our mouse model. Therefore, our preliminary studies simultaneously
generated a new mouse model for B/M MPAL, and identified a novel role of Sirt1 in this malignancy. In this
proposal, we will further characterize this mouse model and test the effect of targeting SIRT1 on B/M MPAL. In
specific aim 1, we will characterize genome-wide mutations and epigenetic alterations in mouse B/M MPAL for
comparison with adult human B/M MPAL. In specific aim 2, we will determine the effect of inhibiting Sirt1 and its
metabolic pathways for hematopoietic stem cell aging on B/M MPAL in the mouse model and adult human B/M
MPAL samples. Successful completion of this proposal will validate a novel mouse model of B/M MPAL for future
mechanistic studies and testing therapeutic intervention, advance our understanding of aging effect on adult B/M
MPAL, and identify new therapeutic targets to improve treatment of this devastating disease.