Commitment to the B-lymphoid lineage depends on the transcription factor Pax5

Nutt, Stephen; Heavey, Barry; Rolink, Antonius; Busslinger, Meinrad

doi:10.1038/35005514

Cited by 282 publications

(476 citation statements)

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“…[19][20][21] PAX5 is required to maintain B-lymphocyte identity 22,23 and its expression suppresses the expression of genes that orchestrate differentiation along other lineages. 24 Coupled with its important role in Blineage identity, the findings in this study confirm that it is also a robust and reliable immunohistologic marker whose tissue-specific expression in B cells can be exploited in routine surgical pathology diagnosis. The two cases of 'undifferentiated neoplasms' in which we detected PAX5 expression posed many challenges at the time of original diagnosis.…”

Section: Pax5 In Undifferentiated Neoplasmssupporting

confidence: 71%

The utility of PAX5 immunohistochemistry in the diagnosis of undifferentiated malignant neoplasms

et al. 2007

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PAX5 is a B-cell transcription factor whose expression at the protein level is reliably detected by immunohistochemistry in routine biopsies. The purpose of this study was to investigate whether PAX5 immunohistochemistry has diagnostic benefit as a B-cell marker in the work-up of undifferentiated malignant neoplasms. Twenty-five cases previously diagnosed as undifferentiated malignant neoplasms were selected. In addition, 59 hematolymphoid and 884 non-hematolymphoid malignancies were studied such that the specificity of PAX5 immunohistochemistry could be addressed. Two of the 25 (8%) undifferentiated neoplasms showed diffuse staining for PAX5, which indicated a B-cell derivation for these neoplasms that was not appreciated at the time of initial diagnosis. PAX5 staining was detected in the vast majority of hematolymphoid tumors of Bcell derivation but only in 5 of 884 (less than 1%) non-hematolymphoid tumors. Our results further show that PAX5 may be the only detectable marker of B lineage in lymphomas that lack or show equivocal CD45RB and CD20 expression. We conclude that the addition of PAX5 to a panel of immunohistologic markers used in the interrogation of undifferentiated neoplasms is of diagnostic benefit. Its expression can also facilitate the diagnosis of classical and nodular lymphocyte-predominant Hodgkin lymphoma with atypical morphologic and immunohistologic features. Lastly, we have shown that the lack of its expression at the protein level in many epithelial and mesenchymal neoplasms renders PAX5 expression an extremely specific marker of the B lineage. Keywords: PAX5; B cell; non-Hodgkin lymphoma; Hodgkin lymphoma; undifferentiated neoplasm PAX5 (B-cell-specific activator protein, BSAP) is a member of the paired box domain gene family that encodes nuclear transcription factors important in development, differentiation, cell migration and proliferation. 1,2 PAX5 protein is expressed as a nuclear marker in B-lineage cells that span the differentiation spectrum from precursor B cells to early plasma cells. 3,4 The expression of PAX5 protein is also a useful lineage-specific marker in hematopoietic neoplasms arising from B cells. [5][6][7][8] Staining for PAX5 has additional utility in the diagnosis of B-cell malignancies that lack expression of commonly used pan-B-cell markers such as CD20 and CD79a. 9 In addition to its expression in B cells, PAX5 protein and/or mRNA has been reported to be expressed in normal and neoplastic cell types in the central nervous system, testis and bladder. 3,[10][11][12][13][14][15] B-cell malignancies may express PAX5 in the absence of expression of other pan-B-cell markers, suggesting that the inclusion of PAX5 in a panel of antibodies to assess undifferentiated malignant neoplasms may have diagnostic benefit. To address this possibility, we studied examples previously diagnosed as undifferentiated malignant neoplasms for PAX5 expression by immunohistologic methods. Hodgkin and non-Hodgkin lymphomas (NHLs) that lacked or showed equivocal staining for CD20 were also i...

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Section: Pax5 In Undifferentiated Neoplasmssupporting

confidence: 71%

The utility of PAX5 immunohistochemistry in the diagnosis of undifferentiated malignant neoplasms

et al. 2007

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“…Pax5 -/-pro-B cells rapidly up-regulate c-kit expression upon Notch signaling Progenitor B (pro-B) cells derived from the bone marrow of Pax5-deficient mice are unable to generate B cells but, unlike wild-type pro-B cells, have the capacity to generate various other hematopoietic cells, including T cells [13,14]. The potential of Pax5 -/-pro-B cells to generate T cells has been demonstrated in vivo, by transplanting them into RAG-deficient mice [13], and in vitro using fetal thymus organ cultures (Rolink et al, unpublished results) and recently using the OP9-DL1 coculture system [12].…”

Section: Resultsmentioning

confidence: 99%

Critical role for c‐kit (CD117) in T cell lineage commitment and early thymocyte development in vitro

Massa¹,

Balc̆iūnaite²,

Ceredig³

et al. 2006

Eur J Immunol

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The precise roles played by the transmembrane receptor tyrosine kinase c-kit and its ligand stem cell factor in early T cell development are difficult to study. Using cloned Pax5-deficient progenitor B cells, we show that following Notch signaling, which induces their commitment to the T cell developmental pathway, c-kit expression is rapidly up-regulated at both the transcriptional and cell surface level. Using either an anti-c-kit monoclonal antibody or Gleevec, a pharmacological inhibitor of c-kit signaling, we show that the Notch-induced T cell differentiation of either Pax5-deficient progenitor B cells, or the equivalent cell from the bone marrow of normal mice, is strictly dependent on c-kit signaling, whereas the differentiation of normal progenitors into the B cell lineage is not. Moreover, we show that the Notch and IL-7 signalinginduced proliferation and differentiation of CD44 + CD25 -c-kit high and CD44 + CD25 + ckit high thymocytes along the T cell, but not natural killer cell or macrophage, pathway also requires c-kit signaling, whereas the Notch-induced proliferation and differentiation of CD44 -CD25 + c-kit int cells along the T cell pathway is independent of c-kit. These results further highlight the complex inter-relationships existing between c-kit, Notch and IL-7 receptor signaling that control the proliferation and differentiation of early T cell progenitors.

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“…In early stages, both PU.1 and Ikaros control the balance between myeloid or lymphoid commitment of MMPs through regulation of different signaling receptors (FLT3, c-KIT and IL-7R) [157][158][159] . More committed, earliest B cell progenitor transition to pro-B cell depends on addi-tional transcription factors (E2A, EBF, PAX5 and BCL11A), which coordinately activate appropriate Bcell expression programs and immunoglobulin heavychain gene rearrangements [160][161][162][163][164][165] . (fig.…”

Section: Do Lymphoid Malignancies Arise From Mutations That Deregulatmentioning

confidence: 99%

Somatic stem cells and the origin of cancer

2006

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647Most human cancers derive from a single cell targeted by genetic and epigenetic alterations that initiate malignant transformation. Progressively, these early cancer cells give rise to different generations of daughter cells that accumulate additional mutations, acting in concert to drive the full neoplastic phenotype 1,2 . As we have currently deciphered many of the gene pathways disrupted in cancer, our knowledge about the nature of the normal cells susceptible to transformation upon mutation has remained more elusive. Adult stem cells are those that show long-term replicative potential, together with the capacities of self-renewal and multi-lineage differentiation. These stem cell properties are tightly regulated in normal development, yet their alteration may be a critical issue for tumorigenesis. This concept has arisen from the striking degree of similarity noted between somatic stem cells and cancer cells, including the fundamental abilities to self-renew and differentiate. Given these shared attributes, it has been proposed that cancers are caused by transforming mutations occurring in tissue-specific stem cells 3-9 . This hypothesis has been functionally supported by the observation that among all cancer cells within a particular tumor, only a minute cell fraction has the exclusive potential to regenerate the entire tumor cell population 3,10-13 ; these cells with stem-like properties have been termed cancer stem cells. Cancer stem cells can originate from mutation in normal somatic stem cells that deregulate their physiological programs. Alternatively, mutations may target more committed progenitor cells or even mature cells, which become reprogrammed to acquire stem-like functions 14,15 In any case, mutated genes should promote expansion of stem/progenitor cells, thus increasing their predisposition to cancer development by expanding self-renewal and pluripotency over their normal tendency towards relative quiescency and proper differentiation.

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Commitment to the B-lymphoid lineage depends on the transcription factor Pax5

Cited by 282 publications

References 50 publications

The utility of PAX5 immunohistochemistry in the diagnosis of undifferentiated malignant neoplasms

The utility of PAX5 immunohistochemistry in the diagnosis of undifferentiated malignant neoplasms

Critical role for c‐kit (CD117) in T cell lineage commitment and early thymocyte development in vitro

Somatic stem cells and the origin of cancer

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