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Involvement of ID4 (Inhibitor of DNA Binding 4) in Haematopoietic Malignancies

By Palminder Kaur Dusanjh


Chromosomal translocations involving the immunoglobulin heavy chain (IGH) locus have been described in B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). One of these, t (6;14)(p22;q32), involved the Inhibitor of DNA Binding 4 (ID4) gene, resulting in deregulated ID4 expression. Members of the ID family are helix-loop-helix proteins that lack DNA binding domains. They are thought to regulate cellular differentiation and proliferation by binding and sequestering E proteins from their DNA targets. The aim of this thesis was to examine the expression and oncogenic potential of ID4 in B-cells. \ud ID4 expression was detected in a subset of chronic lymphocytic leukaemia (CLL) and BCP-ALL lacking the ID4/IGH chromosomal translocation. ID4 expression defined a subtype of BCP-ALL with a distinctive gene signature. \ud ID4, unlike other members of the ID family is not expressed in normal B-cells. Unexpectedly, ectopic ID4 protein expression in most but not all derived B-cell lines reduced proliferation and induced cell cycle arrest. B-cells in ID4-induced cell cycle arrest showed a partial resistance to apoptosis. Proteomic analysis of cell lines expressing ectopic ID4 showed that ID4 interacted with E proteins, although these data could not be confirmed with endogenous ID4 for technical reasons. Primary normal mouse B lymphocyte progenitors showed impaired B-cell development in an in vitro assay following expression of ID4. In contrast, ID4 cooperated with myc over-expression in inducing proliferation of murine B lymphocyte progenitors. \ud Collectively, these data suggest that ID4 may be a novel genetic “driver” in different subtypes of B-cell malignancy. ID4 may contribute to leukemogenesis of B-cell progenitors by inducing inappropriate gene expression and affecting mitosis. This collectively promotes genetic instability and generates a preleukemic stage

Publisher: University of Leicester
Year: 2011
OAI identifier:

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  1. (2003). A
  2. (2009). A comprehensive analysis of the CDKN2A gene in childhood acute lymphoblastic leukemia reveals genomic deletion, copy number neutral loss of heterozygosity, and association with specific cytogenetic subgroups.
  3. (2003). A conserved transcriptional enhancer regulates RAG gene expression in developing B cells.
  4. A et al (2005). Distinct gene expression profiles determine molecular treatment response in childhood acute lymphoblastic leukemia.
  5. (2005). A mitotic septin scaffold required for Mammalian chromosome congression and segregation.
  6. (2000). A pooled analysis of magnetic fields and childhood leukaemia.
  7. (2006). Aberrant expression of ID2, a suppressor of B-cell-specific gene expression, in Hodgkin's lymphoma.
  8. (2010). Acquisition of genome-wide copy number alterations in monozygotic twins with acute lymphoblastic leukemia.
  9. (2008). Acute lymphoblastic leukaemia.
  10. AJ et al (2010). Rearrangement of CRLF2 is associated with mutation of JAK kinases, alteration of IKZF1, Hispanic/Latino ethnicity, and a poor outcome in pediatric B-progenitor acute lymphoblastic leukemia.
  11. An Id-related helix-loop-helix protein encoded by a growth factor-inducible gene.
  12. An integrated genomic analysis of human glioblastoma multiforme.
  13. Aye T et al (2007). Local increase in thymic stromal lymphopoietin induces systemic alterations in B cell development.
  14. (2001). B cell development pathways.
  15. (2008). B lymphocytes: how they develop and function.
  16. (2009). B-cell acute lymphoblastic leukaemia: towards understanding its cellular origin.
  17. (2009). Balance between Id and E proteins regulates myeloid-versus-lymphoid lineage decisions.
  18. Basson CT et al (2004). Rescue of cardiac defects in id knockout embryos by injection of embryonic stem cells.
  19. (2006). Biologic pathways associated with relapse in childhood acute lymphoblastic leukemia: a Children's Oncology Group study.
  20. (2005). BMP-6 inhibits growth of mature human B cells; induction of Smad phosphorylation and upregulation of Id1.
  21. C et al (2003). Id4 is deregulated by a t(6;14)(p22;q32) chromosomal translocation in a B-cell lineage acute lymphoblastic leukemia.
  22. Calasanz MJ et al (2009). Deregulated expression of cytokine receptor gene, CRLF2, is involved in lymphoid transformation in B-cell precursor acute lymphoblastic leukemia.
  23. (2009). Cariappa A
  24. (1997). Cdk2-dependent phosphorylation of Id2 modulates activity of E2A-related transcription factors.
  25. Cejas P et al (2008). Cdc42 is highly expressed in colorectal adenocarcinoma and downregulates ID4 through an epigenetic mechanism.
  26. (2009). Cell nonautonomous function of Id1 in the hematopoietic progenitor cell niche.
  27. (2004). Ciechanover A
  28. Classification of pediatric acute lymphoblastic leukemia by gene expression profiling.
  29. (1999). Commitment to the Blymphoid lineage depends on the transcription factor Pax5.
  30. (2009). Commonality but diversity in cancer gene fusions.
  31. (1994). Constitutive expression of the Id1 gene impairs mouse B cell development.
  32. (2005). Contingent gene regulatory networks and B cell fate specification.
  33. (2002). Contribution of the helix-loophelix factor Id2 to regulation of vascular smooth muscle cell proliferation.
  34. (2002). Control of pre-BCR signaling by Pax5-dependent activation of the BLNK gene.
  35. (1991). Cyclin is degraded by the ubiquitin pathway.
  36. (2005). D53 (TPD52L1) is a cell cycle-regulated protein maximally expressed at the G2-M transition in breast cancer cells.
  37. (1999). Degradation of Id proteins by the ubiquitin-proteasome pathway.
  38. (2006). Determinants of lymphoid-myeloid lineage diversification.
  39. (2005). Different isoforms of BSAP regulate expression of AID in normal and chronic lymphocytic leukemia B cells.
  40. (2007). Discovery of the Philadelphia chromosome: a personal perspective.
  41. Doxsey SJ et al (2008). Id1 overexpression induces tetraploidization and multiple abnormal mitotic phenotypes by modulating aurora A.
  42. Dubart Kupperschmitt A et al (2000). Regulation of Id gene expression during embryonic stem cell-derived hematopoietic differentiation.
  43. (2009). E and ID proteins branch out.
  44. E et al (2009). Loci on 7p12.2, 10q21.2 and 14q11.2 are associated with risk of childhood acute lymphoblastic leukemia.
  45. (2004). E protein silencing by the leukemogenic AML1-ETO fusion protein.
  46. (2008). E proteins are required to activate germline transcription of the TCR Vbeta8.2 gene.
  47. (2006). E2A and IRF-4/Pip promote chromatin modification and transcription of the immunoglobulin kappa locus in pre-B cells.
  48. (1994). E2A proteins are required for proper B cell development and initiation of immunoglobulin gene rearrangements.
  49. (2009). E2A proteins maintain the hematopoietic stem cell pool and promote the maturation of myelolymphoid and myeloerythroid progenitors.
  50. (1996). E2F1 inhibition of transcription activation by myogenic basic helix-loop-helix regulators.
  51. (2004). Early B cell factor promotes B lymphopoiesis with reduced interleukin 7 responsiveness in the absence of E2A.
  52. (1999). Ectopic expression of E47 or E12 promotes the death of E2A-deficient lymphomas.
  53. (2005). Effect of transcription-factor concentrations on leukemic stem cells.
  54. (1998). Efficient and rapid induction of a chronic myelogenous leukemia-like myeloproliferative disease in mice receiving P210 bcr/abl-transduced bone marrow.
  55. (2004). EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy.
  56. et al (2007). Id3 is a novel regulator of p27kip1 mRNA in early G1 phase and is required for cell-cycle progression.
  57. (1993). Expanded range of 11q13 breakpoints with differing patterns of cyclin D1 expression in B-cell malignancies.
  58. (2006). Expression of novel molecules, MICAL2-PV (MICAL2 prostate cancer variants), increases with high Gleason score and prostate cancer progression.
  59. (2003). Expression of the aldehyde dehydrogenase 2-like gene is controlled by BOB.1/OBF.1 in B lymphocytes.
  60. (1997). Expression of the Id family helix-loop-helix regulators during growth and development in the hematopoietic system.
  61. (2006). Expression of tumor protein D52-like genes in childhood leukemia at diagnosis: clinical and sample considerations.
  62. (1996). Expression patterns of Id1, Id2, and Id3 are highly related but distinct from that of Id4 during mouse embryogenesis.
  63. Fasching K et al (2000). Molecular detection of minimal residual disease is a strong predictive factor of relapse in childhood B-lineage acute lymphoblastic leukemia with medium risk features. A case control study of the International BFM study group.
  64. Fazi F et al (2009). The execution of the transcriptional axis mutant p53, E2F1 and ID4 promotes tumor neo-angiogenesis.
  65. Feeney AJ et al (2000). E2A and EBF act in synergy with the V(D)J recombinase to generate a diverse immunoglobulin repertoire in nonlymphoid cells.
  66. (2007). Fetal B-cell lymphopoiesis and the emergence of B-1-cell potential.
  67. (2009). Forcing cells to change lineages.
  68. Frohling S et al (2008). Id1 is a common downstream target of oncogenic tyrosine kinases in leukemic cells.
  69. (2003). From developmental disorder to heritable cancer: it's all in the BMP/TGF-beta family.
  70. (2010). From hematopoietic progenitors to B cells: mechanisms of lineage restriction and commitment.
  71. (2009). From pathogenesis to treatment of chronic lymphocytic leukaemia.
  72. (2000). Functions of E2A-HEB heterodimers in Tcell development revealed by a dominant negative mutation of HEB.
  73. G et al (2006). Degradation of Id2 by the anaphase-promoting complex couples cell cycle exit and axonal growth.
  74. (2008). Gene expression signatures predictive of early response and outcome in high-risk childhood acute lymphoblastic leukemia: A Children's Oncology Group Study [corrected].
  75. (2007). Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia.
  76. Ghosh A (2009). TOX3 regulates calcium-dependent transcription in neurons.
  77. (2009). Giordano A
  78. Giuliano AE et al (2005). Aberrant hypermethylation of ID4 gene promoter region increases risk of lymph node metastasis in T1 breast cancer.
  79. (2005). Global assessment of promoter methylation in a mouse model of cancer identifies ID4 as a putative tumor-suppressor gene in human leukemia.
  80. (2000). Helix-loop-helix proteins: regulators of transcription in eucaryotic organisms.
  81. (1997). High incidence of T-cell tumors in E2A-null mice and E2A/Id1 double-knockout mice.
  82. Hjalgrim H et al (2003). Birth weight as a risk factor for childhood leukemia: a metaanalysis of 18 epidemiologic studies.
  83. (2005). Homozygous deletions of CDKN2A caused by alternative mechanisms in various human cancer cell lines.
  84. human plasmacytoid dendritic cells depends on the combined action of the basic helix-loop-helix factor E2-2 and the Ets factor Spi-B.
  85. Hwang ST et al (2003). Disruption of Id1 reveals major differences in angiogenesis between transplanted and autochthonous tumors.
  86. Iavarone A (2000). Id2 is a retinoblastoma protein target and mediates signalling by Myc oncoproteins.
  87. Iavarone A (2005). Id2 mediates tumor initiation, proliferation, and angiogenesis in Rb mutant mice.
  88. (2005). Id family of helix-loop-helix proteins in cancer.
  89. (2001). Id helix-loophelix proteins antagonize pax transcription factor activity by inhibiting DNA binding.
  90. (2006). Id proteins expression in prostate cancer: high-level expression of Id-4 in primary prostate cancer is associated with development of metastases.
  91. (2002). Id-1 stimulates serum independent prostate cancer cell proliferation through inactivation of p16(INK4a)/pRB pathway.
  92. Id1 restrains myeloid commitment, maintaining the self-renewal capacity of hematopoietic stem cells.
  93. (2008). Id2 intrinsically regulates lymphoid and erythroid development via interaction with different target proteins.
  94. (2004). Id2 is dispensable for myc-induced lymphomagenesis.
  95. (2004). Id2 is dispensable for Mycinduced epidermal neoplasia.
  96. (2002). Id2 negatively regulates B cell differentiation in the spleen.
  97. (1996). Id2 specifically alters regulation of the cell cycle by tumor suppressor proteins.
  98. (2005). Id3 induces growth arrest and caspase-2-dependent apoptosis in B lymphocyte progenitors.
  99. (2001). Id3 inhibits B lymphocyte progenitor growth and survival in response to TGF-beta.
  100. (2005). Id4 is required for the correct timing of neural differentiation.
  101. (2006). Id4 messenger RNA and estrogen receptor expression: inverse correlation in human normal breast epithelium and carcinoma.
  102. (2003). Id4 regulates mammary epithelial cell growth and differentiation and is overexpressed in rat mammary gland carcinomas.
  103. (2004). Id4 regulates neural progenitor proliferation and differentiation in vivo.
  104. (2005). Identification of ID-1 as a potential target gene of MMSET in multiple myeloma.
  105. (2001). Identification of Id4 as a regulator of BRCA1 expression by using a ribozyme-library-based inverse genomics approach.
  106. (1994). Idrelated genes encoding helix-loop-helix proteins are required for G1 progression and are repressed in senescent human fibroblasts.
  107. Immunoglobulin heavy chain locus chromosomal translocations in B-cell precursor acute lymphoblastic leukemia: rare clinical curios or potent genetic drivers?
  108. (1999). Impaired immune responses and B-cell proliferation in mice lacking the Id3 gene.
  109. (2006). Infection, immune responses and the aetiology of childhood leukaemia.
  110. (2004). Infections and immune factors in cancer: the role of epidemiology.
  111. (2009). Inhibitor of differentiation 4 (Id4) is a potential tumor suppressor in prostate cancer.
  112. (2008). Initiating and cancer-propagating cells in TEL-AML1-associated childhood leukemia.
  113. (2008). Instructive role of the transcription factor E2A in early B lymphopoiesis and germinal center B cell development.
  114. (1984). Interleukin-3 supports growth of mouse pre-B-cell clones in vitro.
  115. (2003). Intracellular redistribution of nuclear and nucleolar proteins during differentiation of 32D murine hemopoietic cells.
  116. (2006). Intrinsic inhibition of transcription factor
  117. (2003). is the key to AID gene expression.
  118. Kazemier KM et al (2004). Gene-expression patterns in drug-resistant acute lymphoblastic leukemia cells and response to treatment.
  119. (1979). Kubonishi I et al
  120. (2006). Lasorella A
  121. Leung SC et al (2008). Id-1 promotes chromosomal instability through modification of APC/C activity during mitosis in response to microtubule disruption.
  122. LJ et al (2005). Regulation of cyclin expression and cell cycle progression in breast epithelial cells by the helix-loop-helix protein Id1.
  123. Locksley R et al (2008). Transcription factor E2-2 is an essential and specific regulator of plasmacytoid dendritic cell development.
  124. Loraine Karran E, Nagel I et al (2008). t(6;14)(p22;q32): a new recurrent IGH@ translocation involving ID4 in B-cell precursor acute lymphoblastic leukemia (BCP-ALL).
  125. (2007). Loss of bHLH transcription factor E2A activity in primary effusion lymphoma confers resistance to apoptosis.
  126. (2003). Mad upregulation and Id2 repression accompany transforming growth factor (TGF)-beta-mediated epithelial cell growth suppression.
  127. (2005). Maternal diet and infant leukemia: the DNA topoisomerase II inhibitor hypothesis: a report from the children's oncology group.
  128. (2006). Mechanism and control of V(D)J recombination at the immunoglobulin heavy chain locus.
  129. (2004). mediated by the COP9 signalosome.
  130. Microarray-based classification of a consecutive series of 121 childhood acute leukemias: prediction of leukemic and genetic subtype as well as of minimal residual disease status.
  131. (2001). Molecular cloning and characterization of a zinc finger protein involved in Id-1-stimulated mammary epithelial cell growth.
  132. (2005). Molecular genetics of acute lymphoblastic leukemia.
  133. (2006). Molecular processes of chromosome 9p21 deletions causing inactivation of the p16 tumor suppressor gene in human cancer: deduction from structural analysis of breakpoints for deletions.
  134. (2010). Multiple E2F-induced microRNAs prevent replicative stress in response to mitogenic signalling.
  135. (1996). Nuclear localization and regulation of Id protein through an E protein-mediated chaperone mechanism.
  136. (2005). Nucleo-cytoplasmic shuttling of Id2, a negative regulator of basic helix-loop-helix transcription factors.
  137. Oh SM et al (2000). Molecular mechanism of staurosporine-induced apoptosis in osteoblasts.
  138. Opposing effects of Ets and Id proteins on p16INK4a expression during cellular senescence.
  139. Orr-Weaver TL (2008). Regulation of APC/C activators in mitosis and meiosis.
  140. (2005). Ottmann OG et al
  141. (2007). Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study.
  142. Park HJ et al (2008). Inhibitor of differentiation 4 drives brain tumor-initiating cell genesis through cyclin E and notch signaling.
  143. (2007). Pax5: the guardian of B cell identity and function.
  144. (1999). Positive and negative regulation of V(D)J recombination by the E2A proteins.
  145. (2000). Presence of the P2RY8-CRLF2 rearrangement is associated with a poor prognosis in non-high-risk precursor B-cell acute lymphoblastic leukemia in children treated according to the ALL-BFM
  146. (1986). RCHACV: a lymphoblastic leukemia cell line with chromosome translocation 1;19 and trisomy 8.
  147. (2001). Real-time reverse transcription polymerase chain reaction detection and quantification of t(1;19) (E2A-PBX1) fusion genes associated with leukaemia.
  148. (2009). Rearrangement of CRLF2 in B-progenitor- and Down syndromeassociated acute lymphoblastic leukemia.
  149. (2004). Receptor editing and marginal zone B cell development are regulated by the helix-loop-helix protein, E2A.
  150. (2009). Recurring mutations found by sequencing an acute myeloid leukemia genome.
  151. (1998). Refinement of the BCL2/immunoglobulin heavy chain fusion gene in t(14;18)(q32;q21) by polymerase chain reaction amplification for long targets.
  152. (1994). Regulation of G1 progression by E2A and Id helix-loop-helix proteins.
  153. (1997). Regulation of Id3 cell cycle function by Cdk-2-dependent phosphorylation.
  154. Regulation of lymphocyte development by cell-type-specific interpretation of Notch signals.
  155. (1997). Regulation of the expression of cyclin-dependent kinase inhibitor p21 by E2A and Id proteins.
  156. (2006). Regulation of the INK4b-ARF-INK4a tumour suppressor locus: all for one or one for all.
  157. (1999). required for neurogenesis, angiogenesis and vascularization of tumour xenografts.
  158. Rodig SJ et al (2009). Functional screening identifies CRLF2 in precursor B-cell acute lymphoblastic leukemia.
  159. (2008). Role of platelet-derived growth factors in physiology and medicine.
  160. (1996). Role of the INK4a locus in tumor suppression and cell mortality.
  161. (2007). Septins regulate actin organization and cell-cycle arrest through nuclear accumulation of NCK mediated by SOCS7.
  162. Sequestration of E12/E47 and suppression of p27KIP1 play a role in Id2-induced proliferation and tumorigenesis.
  163. Steele D et al (2007). BRCA1 dysfunction in sporadic basal-like breast cancer.
  164. (2003). SUMO modification of a novel MAR-binding protein, SATB2, modulates immunoglobulin mu gene expression.
  165. (2009). TGF-beta induces growth arrest in Burkitt lymphoma cells via transcriptional repression of E2F-1.
  166. (2009). The cancer genome.
  167. (2003). The death effector domain protein family.
  168. (2005). The development of imatinib as a therapeutic agent for chronic myeloid leukemia.
  169. (2008). The Epstein-Barr virus oncoprotein, latent membrane protein-1, reprograms germinal centre B cells towards a Hodgkin's Reed-Sternberg-like phenotype.
  170. (1994). The expression pattern of Id4, a novel dominant negative helix-loop-helix protein, is distinct from
  171. (2000). The hallmarks of cancer.
  172. (1994). The helix-loop-helix protein Id-2 enhances cell proliferation and binds to the retinoblastoma protein.
  173. (2007). The impact of translocations and gene fusions on cancer causation.
  174. (1990). The pathogenesis of Burkitt's lymphoma.
  175. (1990). The protein Id: a negative regulator of helix-loop-helix DNA binding proteins.
  176. (2000). The role of immunoglobulin translocations in the pathogenesis of B-cell malignancies.
  177. (2008). The Rsu-1-PINCH1-ILK complex is regulated by Ras activation in tumor cells.
  178. (2009). The TEL-AML1 leukemia fusion gene dysregulates the TGF-beta pathway in early B lineage progenitor cells.
  179. (2007). The transcriptional regulation of B cell lineage commitment.
  180. (2009). Three homologous ArfGAPs participate in coat protein I-mediated transport.
  181. (2002). TOX: an HMG box protein implicated in the regulation of thymocyte selection.
  182. (2003). TRAIL-induced signalling and apoptosis.
  183. (2008). Transcription factor EBF restricts alternative lineage options and promotes B cell fate commitment independently of Pax5.
  184. (2003). Transcriptional profiling identifies Id2 function in dendritic cell development.
  185. Transcriptional profiling of human hematopoiesis during in vitro lineage-specific differentiation.
  186. Trappey AK et al (2009). Towards understanding the mode of action of the multifaceted cell adhesion receptor CD146.
  187. Tsai S et al (2005). IL-3 induces inhibitor of DNA-binding protein-1 in hemopoietic progenitor cells and promotes myeloid cell development.
  188. (2004). UbiquitinProteasome-mediated degradation of Id1 is modulated by MyoD.

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