Ordering human CD34+CD10-CD19+ pre/pro-B-cell and CD19- common lymphoid progenitor stages in two pro-B-cell development pathways.
Studies here respond to two long-standing questions: Are human "pre/pro-B" CD34(+)CD10(-)CD19(+) and "common lymphoid progenitor (CLP)/early-B" CD34(+)CD10(+)CD19(-) alternate precursors to "pro-B" CD34(+)CD19(+)CD10(+) cells, and do the pro-B cells that arise from these progenitors belong to the same or distinct B-cell development pathways? Using flow cytometry, gene expression profiling, and Ig V(H)-D-J(H) sequencing, we monitor the initial 10 generations of development of sorted cord blood CD34(high)Lineage(-) pluripotential progenitors growing in bone marrow S17 stroma cocultures. We show that (i) multipotent progenitors (CD34(+)CD45RA(+)CD10(-)CD19(-)) directly generate an initial wave of Pax5(+)TdT(-) "unilineage" pre/pro-B cells and a later wave of "multilineage" CLP/early-B cells and (ii) the cells generated in these successive stages act as precursors for distinct pro-B cells through two independent layered pathways. Studies by others have tracked the origin of B-lineage leukemias in elderly mice to the mouse B-1a pre/pro-B lineage, which lacks the TdT activity that diversifies the V(H)-D-J(H) Ig heavy chain joints found in the early-B or B-2 lineage. Here, we show a similar divergence in human B-cell development pathways between the Pax5(+)TdT(-) pre/pro-B differentiation pathway that gives rise to infant B-lineage leukemias and the early-B pathway.
Departamento de Medicina, Universidad de Alcalá, Alcalá de Henares 28805, Spain.
Eva
E
Sanz
Norman
N
Muñoz-A
Jorge
J
Monserrat
Ana
A
Van-Den-Rym
Pedro
P
Escoll
Ismael
I
Ranz
Melchor
M
Alvarez-Mon
Antonio
A
de-la-Hera
D000818:Animals; D018941:Antigens, CD19 / Q000378:metabolism; D018952:Antigens, CD34 / Q000378:metabolism; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology; D001483:Base Sequence; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation; D018920:Coculture Techniques; D004247:DNA / Q000235:genetics; D005312:Fetal Blood / Q000166:cytology / Q000276:immunology; D020869:Gene Expression Profiling; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D006801:Humans; D007231:Infant, Newborn; D015448:Leukemia, B-Cell / Q000235:genetics / Q000276:immunology; D054503:Lymphoid Progenitor Cells / Q000166:cytology* / Q000276:immunology*; D038041:Lymphopoiesis / Q000276:immunology*; D051379:Mice; D018448:Models, Immunological; D015260:Neprilysin / Q000378:metabolism; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology* / Q000276:immunology*; D017154:Stromal Cells / Q000166:cytology
D018941:Antigens, CD19; D018952:Antigens, CD34; D004247:DNA; D015260:Neprilysin