Pax5: A Master Regulator of B Cell Development and Leukemogenesis

doi:10.1016/B978-0-12-385991-4.00005-2

Advances in Immunology

Volume 111, 2011, Pages 179-206

https://doi.org/10.1016/B978-0-12-385991-4.00005-2 Get rights and content

Abstract

The B cell lineage of the hematopoietic system is responsible for the generation of high-affinity antibodies, which provide humoral immunity for protection against foreign pathogens. B cell commitment and development depend on many transcription factors including Pax5. Here, we review the different functions of Pax5 in regulating various aspects of B lymphopoiesis. At B cell commitment, Pax5 restricts the developmental potential of lymphoid progenitors to the B cell pathway by repressing B-lineage-inappropriate genes, while it simultaneously promotes B cell development by activating B-lymphoid-specific genes. Pax5 thereby controls gene transcription by recruiting chromatin-remodeling, histone-modifying, and basal transcription factor complexes to its target genes. Moreover, Pax5 contributes to the diversity of the antibody repertoire by controlling V_H-DJ_H recombination by inducing contraction of the immunoglobulin heavy-chain locus in pro-B cells, which is likely mediated by PAIR elements in the 5′ region of the V_H gene cluster. Importantly, all mature B cell types depend on Pax5 for their differentiation and function. Pax5 thus controls the identity of B lymphocytes throughout B cell development. Consequently, conditional loss of Pax5 allows mature B cells from peripheral lymphoid organs to develop into functional T cells in the thymus via dedifferentiation to uncommitted progenitors in the bone marrow. Pax5 has also been implicated in human B cell malignancies because it can function as a haploinsufficient tumor suppressor or oncogenic translocation fusion protein in B cell precursor acute lymphoblastic leukemia.

Section snippets

Transcriptional regulation of early B cell development

Acquired immunity to foreign pathogens critically depends on functional B and T cells that develop from hematopoietic stem cells (HSCs) in the bone marrow. HSCs first differentiate to lymphoid-primed multipotent progenitors (LMPPs) and common lymphoid progenitors (CLPs), which consist of Ly6D⁻ all lymphoid progenitors (ALPs) and Ly6D⁺ B cell-biased lymphoid progenitors (BLPs; Inlay et al., 2009). ALPs retain the full lymphoid potential as they are able to develop into B, T, NK, and DC cells (

Spatial regulation of V_H-DJ_H recombination by Pax5

The diverse antigen receptor repertoire of B lymphocytes is generated by V(D)J recombination, which assembles the variable regions of immunoglobulin (Ig) genes from discontinuous variable (V), diversity (D), and joining (J) gene segments during B cell development (Perlot and Alt, 2008). The recombination of Ig genes is tightly controlled within the B-lymphoid lineage, as the Ig heavy-chain (Igh) locus undergoes rearrangements in pro-B cells prior to recombination of the Ig light-chain genes Igk

Function of Pax5 in late B cell differentiation

Pax5 is expressed throughout B cell development from the pro-B to the mature B cell stage and is subsequently repressed during terminal plasma cell differentiation (Fuxa and Busslinger, 2007). The function of Pax5 in late B lymphopoiesis has been analyzed in mature B cells by conditional inactivation using the Cd19-Cre, Cd23-Cre, and Aicda-Cre lines. These experiments revealed that Pax5 is essential for the differentiation of all mature B cell types. In particular, the generation of marginal

Tumor suppression function of Pax5

The first evidence for developmental plasticity of B cells was obtained in aging Cd19-Cre Pax5^fl/− mice, which develop aggressive progenitor cell lymphomas that are indistinguishable in their expression of Pax5 target genes from uncommitted Pax5^−/− pro-B cells (Cobaleda et al., 2007a). However, these Pax5-deficient progenitor cell lymphomas differ from Pax5^−/− pro-B cells, as they carry rearrangements at both the Igh and Igk loci, indicating that they must originate by dedifferentiation from

Perspective

In summary, Pax5 fulfills many different and essential functions throughout B cell development, which are now amenable to in-depth analysis by genome-wide sequencing approaches. It will be important to identify the full spectrum of regulated Pax5 target genes in pro-B and mature B cells by ChIP- and RNA-sequencing in combination with conditional Pax5 inactivation, which will define the Pax5-dependent transcriptional network in the two cell types. A logical next step should be the integration of

Acknowledgments

We thank Leonie Smeenk for helpful comments. This work was supported by Boehringer Ingelheim, the Austrian GEN-AU initiative (financed by the Bundesminsterium für Bildung und Wissenschaft), and the European Union Sixth Framework Program FP6 (funding the EuTRACC project). A. E. was the recipient of a long-term EMBO fellowship.

References (129)

G. Bain et al.
E2A proteins are required for proper B cell development and initiation of immunoglobulin gene rearrangements
Cell
(1994)
M. Bousquet et al.
A novel PAX5-ELN fusion protein identified in B-cell acute lymphoblastic leukemia acts as a dominant negative on the wild-type PAX5
Blood
(2007)
L.H. Bussmann et al.
A robust and highly efficient immune cell reprogramming system
Cell Stem Cell
(2009)
T. Chakraborty et al.
Repeat organization and epigenetic regulation of the D_H-Cμ domain of the immunoglobulin heavy-chain gene locus
Mol. Cell
(2007)
Y.-W. Cho et al.
PTIP associates with MLL3- and MLL4-containing histone H3 lysine 4 methyltransferase complex
J. Biol. Chem.
(2007)
C. Cobaleda et al.
Developmental plasticity of lymphocytes
Curr. Opin. Immunol.
(2008)
J.R. Cook et al.
Lack of PAX5 rearrangements in lymphoplasmacytic lymphomas: Reassessing the reported association with t(9;14)
Hum. Pathol.
(2004)
E. Coyaud et al.
Wide diversity of PAX5 alterations in B-ALL: A Groupe Francophone de Cytogénétique Hématologique study
Blood
(2010)
T. Decker et al.
Stepwise activation of enhancer and promoter regions of the B cell commitment gene Pax5 in early lymphopoiesis
Immunity
(2009)
A. Delogu et al.
Gene repression by Pax5 in B cells is essential for blood cell homeostasis and is reversed in plasma cells
Immunity
(2006)

A. Ebert et al.

The distal V_H gene cluster of the Igh locus contains distinct regulatory elements with Pax5 transcription factor-dependent activity in pro-B cells

Immunity

(2011)

A.V. Emelyanov et al.

The interaction of Pax5 (BSAP) with Daxx can result in transcriptional activation in B cells

J. Biol. Chem.

(2002)

E. Ezhkova et al.

Ezh2 orchestrates gene expression for the stepwise differentiation of tissue-specific stem cells

Cell

(2009)

K.T. Greig et al.

Critical roles for c-Myb in lymphoid priming and early B-cell development

Blood

(2010)

J. Hanna et al.

Direct reprogramming of terminally differentiated mature B lymphocytes to pluripotency

Cell

(2008)

T. He et al.

Histone acetyltransferase p300 acetylates Pax5 and strongly enhances Pax5-mediated transcriptional activity

J. Biol. Chem.

(2011)

M. Horcher et al.

Pax5/BSAP maintains the identity of B cells in late B lymphopoiesis

Immunity

(2001)

T. Ikawa et al.

Long-term cultured E2A-deficient hematopoietic progenitor cells are pluripotent

Immunity

(2004)

S. Jhunjhunwala et al.

The 3D structure of the immunoglobulin heavy-chain locus: Implications for long-range genomic interactions

Cell

(2008)

S. Jhunjhunwala et al.

Chromatin architecture and the generation of antigen receptor diversity

Cell

(2009)

K. Kwon et al.

Instructive role of the transcription factor E2A in early B lymphopoiesis and germinal center B cell development

Immunity

(2008)

K.L. Medina et al.

Assembling a gene regulatory network for specification of the B cell fate

Dev. Cell

(2004)

A.M. Morrison et al.

Deregulated PAX-5 transcription from a translocated IgH promoter in marginal zone lymphoma

Blood

(1998)

K.-P. Nera et al.

Loss of Pax5 promotes plasma cell differentiation

Immunity

(2006)

S.L. Nutt et al.

The transcriptional regulation of B cell lineage commitment

Immunity

(2007)

H. Oguro et al.

Poised lineage specification in multipotential hematopoietic stem and progenitor cells by the Polycomb protein Bmi1

Cell Stem Cell

(2010)

V. Parelho et al.

Cohesins functionally associate with CTCF on mammalian chromosome arms

Cell

(2008)

S.R. Patel et al.

The BRCT-domain containing protein PTIP links PAX2 to a histone H3, lysine 4 methyltransferase complex

Dev. Cell

(2007)

T. Perlot et al.

Cis-regulatory elements and epigenetic changes control genomic rearrangements of the IgH locus

Adv. Immunol.

(2008)

N.A. Barlev et al.

A novel human Ada2 homologue functions with Gcn5 or Brg1 to coactivate transcription

Mol. Cell. Biol.

(2003)

W. Born et al.

Rearrangement of IgH genes in normal thymocyte development

J. Immunol.

(1988)

M. Busslinger

Transcriptional control of early B cell development

Annu. Rev. Immunol.

(2004)

M. Busslinger et al.

Deregulation of PAX-5 by translocation of the Eμ enhancer of the IgH locus adjacent to two alternative PAX-5 promoters in a diffuse large-cell lymphoma

Proc. Natl. Acad. Sci. USA

(1996)

G. Cazzaniga et al.

The paired box domain gene PAX5 is fused to ETV6/TEL in an acute lymphoblastic leukemia case

Cancer Res.

(2001)

D. Chowdhury et al.

Stepwise activation of the immunoglobulin μ heavy chain gene locus

EMBO J.

(2001)

C. Cobaleda et al.

Conversion of mature B cells into T cells by dedifferentation to uncommitted progenitors

Nature

(2007)

C. Cobaleda et al.

Pax5: The guardian of B cell identity and function

Nat. Immunol.

(2007)

S.C. Degner et al.

Cutting edge: Developmental stage-specific recruitment of cohesin to CTCF sites throughout immunoglobulin loci during B lymphocyte development

J. Immunol.

(2009)

D. Eberhard et al.

The partial homeodomain of the transcription factor Pax-5 (BSAP) is an interaction motif for the retinoblastoma and TATA-binding proteins

Cancer Res.

(1999)

D. Eberhard et al.

Transcriptional repression by Pax5 (BSAP) through interaction with corepressors of the Groucho family

EMBO J.

(2000)

S.P. Fahl et al.

c-Myb is required for pro-B cell differentiation

J. Immunol.

(2009)

G. Fazio et al.

PAX5/TEL acts as a transcriptional repressor causing down-modulation of CD19, enhances migration to CXCL12, and confers survival advantage in pre-BI cells

Cancer Res.

(2008)

D. Fitzsimmons et al.

Pax-5 (BSAP) recruits Ets proto-oncogene family proteins to form functional ternary complexes on a B-cell-specific promoter

Genes Dev.

(1996)

M. Fuxa et al.

Reporter gene insertions reveal a strictly B lymphoid-specific expression pattern of Pax5 in support of its B cell identity function

J. Immunol.

(2007)

M. Fuxa et al.

Pax5 induces V-to-DJ rearrangements and locus contraction of the immunoglobulin heavy-chain gene

Genes Dev.

(2004)

H. Gao et al.

Opposing effects of SWI/SNF and Mi-2/NuRD chromatin remodeling complexes on epigenetic reprogramming by EBF and Pax5

Proc. Natl. Acad. Sci. USA

(2009)

C.A. Goetz et al.

Restricted STAT5 activation dictates appropriate thymic B versus T cell lineage commitment

J. Immunol.

(2005)

C. Grabher et al.

Notch1 activation in the molecular pathogenesis of T-cell acute lymphoblastic leukaemia

Nat. Rev. Cancer

(2006)

S. Hadjur et al.

Cohesins form chromosomal cis-interactions at the developmentally regulated IFNG locus

Nature

(2009)

B. Heavey et al.

Myeloid lineage switch of Pax5 mutant but not wild-type B cell progenitors by C/EBPα and GATA factors

EMBO J.

(2003)

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Chapter 5 - Pax5: A Master Regulator of B Cell Development and Leukemogenesis

Abstract

Section snippets

Transcriptional regulation of early B cell development

Spatial regulation of VH-DJH recombination by Pax5

Function of Pax5 in late B cell differentiation

Tumor suppression function of Pax5

Perspective

Acknowledgments

Cell

Blood

Cell Stem Cell

Mol. Cell

J. Biol. Chem.

Curr. Opin. Immunol.

Hum. Pathol.

Blood

Immunity

Immunity

Immunity

J. Biol. Chem.

Cell

Blood

Cell

J. Biol. Chem.

Immunity

Immunity

Cell

Cell

Immunity

Dev. Cell

Blood

Immunity

Immunity

Cell Stem Cell

Cell

Dev. Cell

Adv. Immunol.

A novel human Ada2 homologue functions with Gcn5 or Brg1 to coactivate transcription

Mol. Cell. Biol.

Rearrangement of IgH genes in normal thymocyte development

J. Immunol.

Transcriptional control of early B cell development

Annu. Rev. Immunol.

Deregulation of PAX-5 by translocation of the Eμ enhancer of the IgH locus adjacent to two alternative PAX-5 promoters in a diffuse large-cell lymphoma

Proc. Natl. Acad. Sci. USA

The paired box domain gene PAX5 is fused to ETV6/TEL in an acute lymphoblastic leukemia case

Cancer Res.

Stepwise activation of the immunoglobulin μ heavy chain gene locus

EMBO J.

Conversion of mature B cells into T cells by dedifferentation to uncommitted progenitors

Nature

Pax5: The guardian of B cell identity and function

Nat. Immunol.

Cutting edge: Developmental stage-specific recruitment of cohesin to CTCF sites throughout immunoglobulin loci during B lymphocyte development

J. Immunol.

The partial homeodomain of the transcription factor Pax-5 (BSAP) is an interaction motif for the retinoblastoma and TATA-binding proteins

Cancer Res.

Transcriptional repression by Pax5 (BSAP) through interaction with corepressors of the Groucho family

EMBO J.

c-Myb is required for pro-B cell differentiation

J. Immunol.

PAX5/TEL acts as a transcriptional repressor causing down-modulation of CD19, enhances migration to CXCL12, and confers survival advantage in pre-BI cells

Cancer Res.

Pax-5 (BSAP) recruits Ets proto-oncogene family proteins to form functional ternary complexes on a B-cell-specific promoter

Genes Dev.

Reporter gene insertions reveal a strictly B lymphoid-specific expression pattern of Pax5 in support of its B cell identity function

J. Immunol.

Pax5 induces V-to-DJ rearrangements and locus contraction of the immunoglobulin heavy-chain gene

Genes Dev.

Opposing effects of SWI/SNF and Mi-2/NuRD chromatin remodeling complexes on epigenetic reprogramming by EBF and Pax5

Proc. Natl. Acad. Sci. USA

Restricted STAT5 activation dictates appropriate thymic B versus T cell lineage commitment

J. Immunol.

Notch1 activation in the molecular pathogenesis of T-cell acute lymphoblastic leukaemia

Nat. Rev. Cancer

Cohesins form chromosomal cis-interactions at the developmentally regulated IFNG locus

Nature

Myeloid lineage switch of Pax5 mutant but not wild-type B cell progenitors by C/EBPα and GATA factors

EMBO J.

Spatial regulation of V_H-DJ_H recombination by Pax5