Despite significant advances in identifying distinct chromosomal translocations associated with pediatric B- Acute Lymphoblastic Leukemia (B-ALL), why ~20% of patients present with disease that is aggressive, responds poorly to therapy, and is associated with poor survival is unknown. The distinguishing feature of this application is the developmental perspective from which this question is addressed. We propose that in addition to the particular chromosomal translocation, B cell lineage also plays a prominent role in B-ALL progression. While most B cells are generated from B-2 progenitors produced in post-natal bone marrow, a second population of B-1 cells that derive from B-1 progenitors whose production is most robust in the fetus exists. Because B-1 progenitors are highly proliferative cells with low rates of apoptosis, we hypothesize that some childhood B-ALLs are B-1 malignancies and that these exhibit an aggressive clinical course. In an initial, proof of concept experiment, we observed that BCR-ABL transduced B-1 progenitors developed a rapid B-ALL in recipient mice. Experiments in Aim 1 will confirm and extend this observation by harvesting B-1 and B-2 progenitors from TEL -AML1 x Cdkn2a-/- mice, which develop B-ALL at a median of seven months of age, and BCR-ABL transgenic mice, which succumb to an aggressive B-ALL within weeks after birth. These experiments will provide a biological demonstration that B-cell lineage can be a major factor that determines the progression of lymphoblastic leukemia. Studies in Aim 2 will determine if the gene signature of normal B-1 and B-2 progenitors is reflected in the biology of the B-ALL that develops. We will isolate normal B-1 and B-2 progenitors and analyze patterns of gene expression in them using microarray analysis. We will then determine how these signatures are reflected in the B-1 versus B-2 leukemias generated in Aim 1. The expectation is that the genetic network that correlates with the high rate of proliferation and low levels of apoptosis exhibited by normal B-1 progenitors will also be duplicated in aggressive forms of B-ALL. Finally, we will determine if the signatures identified in the aggressive murine tumors have translational potential as early detection markers of sub-types of human B-ALL with similar characteristics. The results of our proposal, which is being submitted in response to PA-08-267, will provide new biological insights into why some forms of B-ALL are particularly aggressive. Moreover, the work has the potential to select a robust set of biomarkers for risk assessment in ALL.
B-Acute Lymphoblastic Leukemia (B-ALL) is the most common pediatric malignancy. Despite significant advances in identifying genetic abnormalities associated with B-Acute Lymphoblastic Leukemia (B-ALL), why ~20% of B-ALL patients present with disease that is aggressive, responds poorly to therapy, and is associated with poor survival is unknown. The aim of this application is to provide a biological explanation for this and identif biomarkers to identify aggressive forms of the disease. This information may ultimately be of value in optimizing treatment regimens.
|Montecino-Rodriguez, Encarnacion; Li, Katy; Fice, Michael et al. (2014) Murine B-1 B cell progenitors initiate B-acute lymphoblastic leukemia with features of high-risk disease. J Immunol 192:5171-8|