B Cell Linker Protein (BLNK) Is a Selective Target of Repression by PAX5-PML Protein in the Differentiation Block That Leads to the Development of Acute Lymphoblastic Leukemia*

PAX5 is a transcription factor that is required for the development and maintenance of B cells. Promyelocytic leukemia (PML) is a tumor suppressor and proapoptotic factor. The fusion gene PAX5-PML has been identified in acute lymphoblastic leukemia with chromosomal translocation t(9;15)(p13;q24). We have reported previously that PAX5-PML dominant-negatively inhibited PAX5 transcriptional activity and impaired PML function by disrupting PML nuclear bodies (NBs). Here we demonstrated the leukemogenicity of PAX5-PML by introducing it into normal mouse pro-B cells. Arrest of differentiation was observed in PAX5-PML-introduced pro-B cells, resulting in the development of acute lymphoblastic leukemia after a long latency in mice. Among the transactivation targets of PAX5, B cell linker protein (BLNK) was repressed selectively in leukemia cells, and enforced BLNK expression abrogated the differentiation block and survival induced by PAX5-PML, indicating the importance of BLNK repression for the formation of preleukemic state. We also showed that PML NBs were intact in leukemia cells and attributed this to the low expression of PAX5-PML, indicating that the disruption of PML NBs was not required for the PAX5-PML-induced onset of leukemia. These results provide novel insights into the molecular mechanisms underlying the onset of leukemia by PAX5 mutations.

[1]  S. Tsuzuki,et al.  Synergy of Myc, cell cycle regulators and the Akt pathway in the development of aggressive B-cell lymphoma in a mouse model , 2014, Leukemia.

[2]  S. Tsuzuki,et al.  TEL (ETV6)‐AML1 (RUNX1) Initiates Self‐Renewing Fetal Pro‐B Cells in Association with a Transcriptional Program Shared with Embryonic Stem Cells in Mice , 2013, Stem cells.

[3]  M. Farrar,et al.  Ebf1 or Pax5 haploinsufficiency synergizes with STAT5 activation to initiate acute lymphoblastic leukemia , 2011, The Journal of experimental medicine.

[4]  T. Naoe,et al.  PAX5–PML acts as a dual dominant-negative form of both PAX5 and PML , 2011, Oncogene.

[5]  J. Qiu,et al.  The reduced and altered activities of PAX5 are linked to the protein–protein interaction motif (coiled-coil domain) of the PAX5–PML fusion protein in t(9;15)-associated acute lymphocytic leukemia , 2011, Oncogene.

[6]  J. D. Vos,et al.  PAX5 mutations occur frequently in adult B-cell progenitor acute lymphoblastic leukemia and PAX5 haploinsufficiency is associated with BCR-ABL1 and TCF3-PBX1 fusion genes: a GRAALL study , 2009, Leukemia.

[7]  Martin Zimmermann,et al.  Cloning of genes involved in chromosomal translocations by high-resolution single nucleotide polymorphism genomic microarray , 2008, Proceedings of the National Academy of Sciences.

[8]  A. Rolink,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. , 2008, Cancer research.

[9]  R. Siebert,et al.  Identification of PML as novel PAX5 fusion partner in childhood acute lymphoblastic leukaemia , 2007, British journal of haematology.

[10]  P. Brousset,et al.  A novel PAX5-ELN fusion protein identified in B-cell acute lymphoblastic leukemia acts as a dominant negative on wild-type PAX5. , 2007, Blood.

[11]  Christopher B. Miller,et al.  Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia , 2007, Nature.

[12]  Graham Dellaire,et al.  PML nuclear bodies: dynamic sensors of DNA damage and cellular stress , 2004, BioEssays : news and reviews in molecular, cellular and developmental biology.

[13]  F. Hayakawa,et al.  Phosphorylation of PML by mitogen-activated protein kinases plays a key role in arsenic trioxide-mediated apoptosis. , 2004, Cancer cell.

[14]  M. Busslinger.  Transcriptional control of early B cell development. , 2004, Annual review of immunology.

[15]  H. Saito,et al.  Functional regulation of GATA‐2 by acetylation , 2003, Journal of leukocyte biology.

[16]  C. Garvie,et al.  Requirements for selective recruitment of Ets proteins and activation of mb-1/Ig-alpha gene transcription by Pax-5 (BSAP). , 2003, Nucleic acids research.

[17]  S. Rivella,et al.  A novel murine model of Cooley anemia and its rescue by lentiviral-mediated human beta-globin gene transfer. , 2003, Blood.

[18]  M. Schebesta,et al.  Control of pre-BCR signaling by Pax5-dependent activation of the BLNK gene. , 2002, Immunity.

[19]  M. Nussenzweig,et al.  B Cell Progenitors Are Arrested in Maturation but Have Intact VDJ Recombination in the Absence of Ig-α and Ig-β1 , 2002, The Journal of Immunology.

[20]  A. Cheng,et al.  Requirement for B cell linker protein (BLNK) in B cell development. , 1999, Science.

[21]  S J Chen,et al.  Studies on treatment of acute promyelocytic leukemia with arsenic trioxide: remission induction, follow-up, and molecular monitoring in 11 newly diagnosed and 47 relapsed acute promyelocytic leukemia patients. , 1999, Blood.

[22]  E. Yeh,et al.  Pml Is Critical for Nd10 Formation and Recruits the Pml-Interacting Protein Daxx to This Nuclear Structure When Modified by Sumo-1 , 1999, The Journal of cell biology.

[23]  P. Pandolfi,et al.  Pml is essential for multiple apoptotic pathways , 1998, Nature Genetics.

[24]  A. M. Morrison,et al.  Identification of BSAP (Pax‐5) target genes in early B‐cell development by loss‐ and gain‐of‐function experiments , 1998, The EMBO journal.

[25]  A. M. Morrison,et al.  Loss- and gain-of-function mutations reveal an important role of BSAP (Pax-5) at the start and end of B cell differentiation. , 1998, Seminars in immunology.

[26]  P. Pandolfi,et al.  Role of PML in cell growth and the retinoic acid pathway. , 1998, Science.

[27]  A. Dejean,et al.  Conjugation with the ubiquitin‐related modifier SUMO‐1 regulates the partitioning of PML within the nucleus , 1998, The EMBO journal.

[28]  C. Niu,et al.  Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): I. As2O3 exerts dose-dependent dual effects on APL cells. , 1997, Blood.

[29]  H. de Thé,et al.  Arsenic-induced PML targeting onto nuclear bodies: implications for the treatment of acute promyelocytic leukemia. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[30]  B. Koller,et al.  Abnormal B lymphocyte development, activation, and differentiation in mice that lack or overexpress the CD19 signal transduction molecule. , 1995, Immunity.

[31]  N. Stuurman,et al.  The t(15;17) translocation alters a nuclear body in a retinoic acid‐reversible fashion. , 1994, The EMBO journal.

[32]  R. Evans,et al.  A novel macromolecular structure is a target of the promyelocyte-retinoic acid receptor oncoprotein , 1994, Cell.

[33]  Maria Carmo-Fonseca,et al.  Retinoic acid regulates aberrant nuclear localization of PML-RARα in acute promyelocytic leukemia cells , 1994, Cell.

[34]  M. Busslinger,et al.  The promoter of the CD19 gene is a target for the B-cell-specific transcription factor BSAP , 1992, Molecular and cellular biology.