Wipping p53 into subservience in B-cell development

In this issue of Blood, Yi et al reveal an important role for the protein phosphatase Wip1 (PPM1D) in the regulation of B-cell homeostasis.¹  Mice deficient in the Wip1 gene display increased apoptosis in the pre–B-cell compartment and a reduction in peripheral B-cell numbers, a phenotype exacerbated with age and upon serial transplantations of bone marrow (BM) cells.¹  Even though Wip1 has the ability to modulate multiple signaling pathways in the cell, the restoration of B-cell numbers upon deletion of the p53 gene¹  suggests that an autoregulatory loop between p53 and Wip1 is of importance to maintain normal production of B lymphocytes.

The development of mature B lymphocytes from hematopoietic stem cells in the BM is a complex process in which proliferation and expansion need to be coordinated with DNA recombination events as well as the selection of functional progenitor cells (see figure). In order to better understand the molecular interplay underlying the homeostatic expansion of B-lymphoid cells, Yi and colleges explored the functional role of the p53-activated serine/threonine protein phosphatase Wip1²  in the formation and expansion of B-lymphoid cells.¹ Wip1 was originally identified as a p53 target gene,²  and subsequent experiments revealed that this protein acts in an autoregulatory loop to reduce the functional activity of p53.³  The current report reveals that in the absence of Wip1, the formation of the pre–B-cell compartment is impaired.¹  The early pre–B-cell stage represents one of the major windows for cell proliferation in early B-cell development, as coordinated interleukin-7 and pre–B-cell receptor signaling drives the proliferation of cells carrying a functional immunoglobulin (Ig) heavy-chain gene,⁴  and it is therefore reasonable that targeting of this developmental stage impairs the formation of mature B-lineage cells. p53 can block cell-cycle progression by induction of p21 expression; however, deletion of p21 could not rescue B-cell development in Wip1-deficient mice, arguing against the idea that the loss of pre–B cells would be due to a disruption of cell-cycle progression.¹  Analysis of the cell-cycle status of defined B-cell compartments supported this notion, because no significant differences in G₁-S-G₂ composition could be detected. Rather, the phenotype appeared to be related to an increased apoptosis in the pre–B-cell compartment, a phenotype that could be rescued by loss of p53 function, indicating a need for harnessing p53 to control apoptosis in early B-cell development.

p53 is activated by DNA damage, and it is tempting to speculate that Ig rearrangements, known to induce double-strand breaks and a DNA damage response, would result in increased p53 activity that needs to be modulated by Wip1. However, while a CDK/cyclin A–mediated degradation of RAG-2 restricts Ig recombination to the G₁ phase of the cell cycle,⁵  Wip1 has been suggested to act mainly in G₂ phase, where the protein is able to potently release a cell-cycle block.⁶  Furthermore, DNA damage generated during G₁ phase would likely result in sustained p21 expression and a cell-cycle block at the G₁-S transition. Hence, the p53 response modulated by Wip1 is unlikely to be related to the Ig recombination process per se but rather to other DNA-damaging events occurring during the replication process.

The reduction in pre–B-cell numbers in Wip1-deficient mice could not be compensated for by peripheral expansion of mature B cells because the reduction in cell numbers was consistent in blood, lymph nodes, and spleen,¹  possibly indicating an additional need of modulated p53 activity in peripheral cells. Even though Wip1 deficiency results in impaired T-cell development⁷  and an expanded peripheral pool of neutrophils⁸  that could potentially impact the peripheral expansion of the mature B-cell compartments, Yi et al use BM chimera experiments to demonstrate that Wip1 deficiency impacts B-cell development in a cell-autonomous manner.¹  The impact of reduced Wip1 activity was further exacerbated upon serial transplantation or aging, suggesting an involvement of immature long-lived progenitor compartments. In line with this notion, the exacerbated phenotype was associated with reduced numbers of pre-pro– and pro–B cells that was not observed to the same extent in young adult mice.¹  In further support of a role for Wip1 in early progenitors, recently published data suggest that regulation of p53 activity by Wip1 impacts long-lived hematopoietic progenitors in the BM.⁹ 

Although there exists an apparent need to harness p53 activity to achieve normal B-cell production, there is likely a need to balance rather than abolish the activity of this protein, because loss of p53 function is a common event in human malignancies. Of special interest in the context of this report is the finding that a mutated or deleted TP53 gene is one of the strongest independent predictors of inferior treatment outcome in childhood B-lineage acute lymphoblastic leukemia.¹⁰  In a situation where the functional dose of a transcription factor like p53 is of critical importance, the use of an autoregulatory loop such as that created by the induction of Wip1 transcription by p53 presents an elegant solution to preserve a high output of normal cells while still preventing uncontrolled malignant proliferation of progenitor cells. Therefore, the extended insight to Wip1 function provided by this report is an important contribution to our understanding of regulatory events in early B-lymphocyte development.