Using novel murine models based on retroviral transduction of bone marrow progenitors, we made a surprising discovery that the resultant neoplasms are prone to losing their B-cell identity and converting into myeloid cancers by virtue of extinguishing the key lineage fidelity transcriptions factor PAX5. Since PAX5 loss entails silencing of key BCR components (e.g., CD19), we were able to address the role of the Pax5-BCR axis in hematological malignancies.
We were the first to formally prove that PAX5 promotes neoplastic growth through stimulation of BCR signaling. Subsequently, we made an unexpected discovery that CD19 can drive drives neoplastic growth in the absence of the BCR, by virtue of recruiting PI3 kinase and stabilizing the MYC protein.
This finding has particular relevance for acute lymphoblastic leukemias derived from immature pro-B-cells. On the other hand, in post-germinal center neoplasms (e.g., diffuse large B-cell lymphoma), activation of MYC by the CD19-BCR complex starts a positive feed-forward loop, whereby MYC boosts BCR signaling by down-modulating its antagonists known as ITIM proteins.