Signaling proteins and transcription factors in normal and malignant early B cell development

Abstract

B cell development starts in bone marrow with the commitment of hematopoietic progenitors to the B cell lineage. In murine models, the IL-7 and preBCR receptors, and the signaling pathways and transcription factors that they regulate, control commitment and maintenance along the B cell pathway. E2A, EBF1, PAX5, and Ikaros are among the most important transcription factors controlling early development and thereby conditioning mice homeostatic B cell lymphopoiesis. Importantly, their gain or loss of function often results in malignant development in humans, supporting conserved roles for these transcription factors. B cell acute lymphoblastic leukemia is the most common cause of pediatric cancer, and it is characterized by unpaired early B cell development resulting from genetic lesions in these critical signaling pathways and transcription factors. Fine mapping of these genetic abnormalities is allowing more specific treatments, more accurately predicting risk profiles for this disease, and improving survival rates.

Figure 1

B cell development in adult mammals starts in bone marrow with the commitment of hematopoietic stem cells (HSCs) to the B cell lineage and ends with formation of mature B cells in peripheral secondary lymphoid organs (e.g., the spleen). It is the sequential expression and assembly of the components of the B cell antigen receptor (BCR) what defines each developmental stage. The first stage exhibiting commitment to the B cell lineage is the proB, and here the immunoglobulin heavy chain is in the process of recombination, and the signaling proteins Igα and Igβ are in surface forming complexes with chaperon proteins like calnexin (the proBCR). The next developmental stage, the preB, happens after the heavy chain was successfully recombined and the preBCR is assembled. In this stage, the light chain is recombined and unrearranged heavy chain alleles are excluded. After light chain recombination and pairing with the heavy chain and Igα and Igβ the mature BCR is formed, the B cell is in the immature (in bone marrow) and transitional (in periphery) stages. Here, B cell mechanisms of self-tolerance are active allowing self- and nonself-recognition by the mature B cell. Transition to the mature stage happens if the BCR of the immature/transitional B cell does not find its cognate antigen after several days of bone marrow and peripheral trafficking.

Figure 2

(a) The Ig heavy and light chain genes are comprised of constant and variable regions, where the variable region is formed by an n number of segments termed V (variable), D (diversity), and J (joining) in the heavy chain and by segments V and J in the light chain. These segments are brought together by a site-specific recombination process termed VDJ recombination responsible for the extensive repertoire of BCR specificities. There are two loci for light chain, κ and λ. Here, all the loci are shown in germline configuration, previous to the process of VDJ recombination. (b) The early stages of B cell development are differentiated by the process of VDJ recombination, and the heavy (IgH) and light (IgL) chains are recombined in the proB and preB stages, respectively. Each stage is further subdivided according to the sequential assembly of the VDJ segments. Replication and recombination processes are mutually exclusive as denoted by the circular arrows and VDJ signs inside the cell. Dashed lines separating proB and preB stages indicate checkpoints where signaling from the preBCR and BCR is required for positive selection and progression along the B cell maturation pathway. Continuous lines indicate the main receptors controlling each developmental stage. The differential intensity in the IL-7 green line indicates the sub-stages where a higher or lower concentration of the IL-7R ligand is required.

Figure 3

Homeostatic and leukemic expression of receptors, signaling proteins, and transcription factors along the B cell pathway. Developmental stages are indicated starting with the hematopoietic stem cell (HSC), the common lymphoid progenitor (CLP), and into the B cell pathway, stages proB, preB, and mature B cells. Normal gene expression along the developmental pathway is indicated with blue bars, and expression dependency between proteins is indicated with arrows. Most common modified forms of these receptors, signaling proteins, and transcription factors associated with acute lymphoblastic leukemia are also indicated.