The common lymphoid progenitor (CLP) responsible for the formation of T, B and NK cells is derived from a hematopoietic stem cell that is first identified in the embryonic aorto-gonad- mesonephros, a descendent of the mesoderm. The signals to initiate and regulate development are due to the control imposed by a variety of marrow stromal cells, transcription factors, and coordinated regulation by the nervous system, extracellular matrix, cytokines and adipocytes found in the bone marrow microenvironment. The general consensus of the ontological steps leading to production of naïve B-cells is summarized as follows; the earliest identifiable committed B-cells derived from the CLP are called progenitor (Pro) B-cells. Pro B-cells arise after obligate stimulation by the transcription factor PAX-5, which engenders CD19 production. These CD34+ CD19+ CD10+ CD38+ TdT+ expressing cells lack the pre-B-cell receptor or surface immunoglobulin (Ig) and initiate VDJ heavy chain rearrangements independent of any antigenic exposure. Pro B cells differentiate into CD34- CD19+ CD10+ CD38+ TdT- precursor (Pre) B-cells that acquire cytoplasmic and then surface mu heavy chain with a transient surrogate immunoglobulin light chain. Next, a CD19+ CD10-CD38- immature B-cell expresses surface IgM+ and physiologic light chain. Ultimately, CD19+ CD20+ B-cells co-expressing IgM and IgD heavy chains exit the bone marrow as transitional B-cells and home to secondary lymphoid organs as naive B-cells.

We are interested in the use of probability state modeling to quantify the locations of antigen modulations during the ontological development of human B-cells to determine the discrete progenitor and B-cell stages that occur during normal maturation. We will use this information to study and predict minimal residual disease in patients with B-lymphoblastic lymphoma.