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儿童急性淋巴细胞白血病PAX5基因的研究进展
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Abstract:
急性淋巴细胞白血病是儿童常见的血液系统恶性肿瘤。最常见的遗传改变基因之一是PAX5基因。PAX5基因的表达贯穿B细胞发育的整个过程，其改变包括拷贝数变异、重排、基因内扩增、选择性剪切和点突变等。PAX5与伴侣基因产生融合蛋白通过干扰白血病细胞中正常PAX5蛋白的转录活性而发挥竞争性抑制剂的作用。PAX5基因相关的B-ALL亚型PAX5 P80R在儿童病例中与较差预后相关，PAX5alt亚型患者被归为高风险的频率高于标准风险。本文就PAX5基因在急性淋巴细胞白血病中的发病机制、融合基因及治疗策略进行综述。
Acute lymphoblastic leukemia (ALL) is a common hematologic malignancy in children, with one of the most frequently altered genes being the PAX5 gene. The expression of the PAX5 gene is involved throughout the entire process of B-cell development, and its alterations include copy number variations, rearrangements, intragenic amplifications, alternative splicing, and point mutations. The fusion proteins formed by PAX5 and its partner genes act as competitive inhibitors by interfering with the normal transcriptional activity of the PAX5 protein in leukemic cells. The PAX5 gene-related B-ALL subtype PAX5 P80R was associated with a poorer prognosis in childhood cases, and patients with the PAX5alt subtype were classified as high risk more often than the standard risk. This review summarizes the role of the PAX5 gene in the pathogenesis of ALL, its fusion genes, and related therapeutic strategies.
| [1] | Mullighan, C.G., Goorha, S., Radtke, I., Miller, C.B., Coustan-Smith, E., Dalton, J.D., et al. (2007) Genome-Wide Analysis of Genetic Alterations in Acute Lymphoblastic Leukaemia. Nature, 446, 758-764. https://doi.org/10.1038/nature05690 |
| [2] | Gu, Z., Churchman, M.L., Roberts, K.G., Moore, I., Zhou, X., Nakitandwe, J., et al. (2019) Pax5-Driven Subtypes of B-Progenitor Acute Lymphoblastic Leukemia. Nature Genetics, 51, 296-307. https://doi.org/10.1038/s41588-018-0315-5 |
| [3] | Li, Z., Lee, S.H.R., Chin, W.H.N., Lu, Y., Jiang, N., Lim, E.H., et al. (2021) Distinct Clinical Characteristics of DUX4-and PAX5-Altered Childhood B-Lymphoblastic Leukemia. Blood Advances, 5, 5226-5238. https://doi.org/10.1182/bloodadvances.2021004895 |
| [4] | Simmons, S., Knoll, M., Drewell, C., Wolf, I., Mollenkopf, H., Bouquet, C., et al. (2012) Biphenotypic B-Lymphoid/Myeloid Cells Expressing Low Levels of PAX5: Potential Targets of BAL Development. Blood, 120, 3688-3698. https://doi.org/10.1182/blood-2012-03-414821 |
| [5] | Mikkola, I., Heavey, B., Horcher, M. and Busslinger, M. (2002) Reversion of B Cell Commitment Upon Loss of PAX5 Expression. Science, 297, 110-113. https://doi.org/10.1126/science.1067518 |
| [6] | Schebesta, A., McManus, S., Salvagiotto, G., Delogu, A., Busslinger, G.A. and Busslinger, M. (2007) Transcription Factor PAX5 Activates the Chromatin of Key Genes Involved in B Cell Signaling, Adhesion, Migration, and Immune Function. Immunity, 27, 49-63. https://doi.org/10.1016/j.immuni.2007.05.019 |
| [7] | Chan, L.N., Chen, Z., Braas, D., Lee, J., Xiao, G., Geng, H., et al. (2017) Metabolic Gatekeeper Function of B-Lymphoid Transcription Factors. Nature, 542, 479-483. https://doi.org/10.1038/nature21076 |
| [8] | Somasundaram, R., Jensen, C.T., Tingvall-Gustafsson, J., Åhsberg, J., Okuyama, K., Prasad, M., et al. (2021) EBF1 and PAX5 Control Pro-B Cell Expansion via Opposing Regulation of the Myc Gene. Blood, 137, 3037-3049. https://doi.org/10.1182/blood.2020009564 |
| [9] | Ramamoorthy, S., Kometani, K., Herman, J.S., Bayer, M., Boller, S., Edwards-Hicks, J., et al. (2020) EBF1 and PAX5 Safeguard Leukemic Transformation by Limiting IL-7 Signaling, Myc Expression, and Folate Metabolism. Genes & Development, 34, 1503-1519. https://doi.org/10.1101/gad.340216.120 |
| [10] | Familiades, J., Bousquet, M., Lafage-Pochitaloff, M., Béné, M., Beldjord, K., de Vos, J., et al. (2009) 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. Leukemia, 23, 1989-1998. https://doi.org/10.1038/leu.2009.135 |
| [11] | Kim, M., Choi, J.E., She, C.J., Hwang, S.M., Shin, H.Y., Ahn, H.S., et al. (2011) PAX5 Deletion Is Common and Concurrently Occurs with CDKN2A Deletion in B-Lineage Acute Lymphoblastic Leukemia. Blood Cells, Molecules, and Diseases, 47, 62-66. https://doi.org/10.1016/j.bcmd.2011.04.003 |
| [12] | Heltemes-Harris, L.M., Willette, M.J.L., Ramsey, L.B., Qiu, Y.H., Neeley, E.S., Zhang, N., et al. (2011) Ebf1 or Pax5 Haploinsufficiency Synergizes with STAT5 Activation to Initiate Acute Lymphoblastic Leukemia. Journal of Experimental Medicine, 208, 1135-1149. https://doi.org/10.1084/jem.20101947 |
| [13] | Prasad, M.A.J., Ungerbäck, J., Åhsberg, J., Somasundaram, R., Strid, T., Larsson, M., et al. (2015) Ebf1 Heterozygosity Results in Increased DNA Damage in Pro-B Cells and Their Synergistic Transformation by Pax5 Haploinsufficiency. Blood, 125, 4052-4059. https://doi.org/10.1182/blood-2014-12-617282 |
| [14] | Martín-Lorenzo, A., Auer, F., Chan, L.N., García-Ramírez, I., González-Herrero, I., Rodríguez-Hernández, G., et al. (2018) Loss of Pax5 Exploits Sca1-Bcr-Ablp190 Susceptibility to Confer the Metabolic Shift Essential for Pb-All. Cancer Research, 78, 2669-2679. https://doi.org/10.1158/0008-5472.can-17-3262 |
| [15] | Kanayama, T., Imamura, T., Mayumi, A., Soma, E., Sakamoto, K., Hayakawa, F., et al. (2020) Functional Analysis of a Novel Fusion Protein PAX5-KIDINS220 Identified in a Pediatric Ph-Like ALL Patient. International Journal of Hematology, 112, 714-719. https://doi.org/10.1007/s12185-020-02944-4 |
| [16] | Poppe, B., de Paepe, P., Michaux, L., Dastugue, N., Bastard, C., Herens, C., et al. (2005) PAX5/IGH Rearrangement Is a Recurrent Finding in a Subset of Aggressive B-NHL with Complex Chromosomal Rearrangements. Genes, Chromosomes and Cancer, 44, 218-223. https://doi.org/10.1002/gcc.20214 |
| [17] | Jurado, S., Fedl, A.S., Jaritz, M., Kostanova-Poliakova, D., Malin, S.G., Mullighan, C.G., et al. (2022) The PAX5-JAK2 Translocation Acts as Dual-Hit Mutation That Promotes Aggressive B-cell Leukemia via Nuclear STAT5 Activation. The EMBO Journal, 41, e108397. https://doi.org/10.15252/embj.2021108397 |
| [18] | Smeenk, L., Fischer, M., Jurado, S., Jaritz, M., Azaryan, A., Werner, B., et al. (2017) Molecular Role of the PAX5-ETV6 Oncoprotein in Promoting B-Cell Acute Lymphoblastic Leukemia. The EMBO Journal, 36, 718-735. https://doi.org/10.15252/embj.201695495 |
| [19] | Fortschegger, K., Anderl, S., Denk, D. and Strehl, S. (2014) Functional Heterogeneity of PAX5 Chimeras Reveals Insight for Leukemia Development. Molecular Cancer Research, 12, 595-606. https://doi.org/10.1158/1541-7786.mcr-13-0337 |
| [20] | Imoto, N., Hayakawa, F., Kurahashi, S., Morishita, T., Kojima, Y., Yasuda, T., et al. (2016) 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. Journal of Biological Chemistry, 291, 4723-4731. https://doi.org/10.1074/jbc.m115.637835 |
| [21] | Jean, J., Kovach, A.E., Doan, A., Oberley, M., Ji, J., Schmidt, R.J., et al. (2022) Characterization of PAX5 Intragenic Tandem Multiplication in Pediatric B-Lymphoblastic Leukemia by Optical Genome Mapping. Blood Advances, 6, 3343-3346. https://doi.org/10.1182/bloodadvances.2021006328 |
| [22] | Zaliova, M., Stuchly, J., Winkowska, L., Musilova, A., Fiser, K., Slamova, M., et al. (2019) Genomic Landscape of Pediatric B-Other Acute Lymphoblastic Leukemia in a Consecutive European Cohort. Haematologica, 104, 1396-1406. https://doi.org/10.3324/haematol.2018.204974 |
| [23] | Busslinger, M., Klix, N., Pfeffer, P., Graninger, P.G. and Kozmik, Z. (1996) Deregulation of PAX-5 by Translocation of the Emu Enhancer of the IgH Locus Adjacent to Two Alternative PAX-5 Promoters in a Diffuse Large-Cell Lymphoma. Proceedings of the National Academy of Sciences, 93, 6129-6134. https://doi.org/10.1073/pnas.93.12.6129 |
| [24] | Sadakane, Y., Zaitsu, M., Nishi, M., Sugita, K., Mizutani, S., Matsuzaki, A., et al. (2006) Expression and Production of Aberrant PAX5 with Deletion of Exon 8 in B-Lineage Acute Lymphoblastic Leukaemia of Children. British Journal of Haematology, 136, 297-300. https://doi.org/10.1111/j.1365-2141.2006.06425.x |
| [25] | Santoro, A., Bica, M.G., Dagnino, L., Agueli, C., Salemi, D., Cannella, S., et al. (2009) Altered mRNA Expression of PAX5 Is a Common Event in Acute Lymphoblastic Leukaemia. British Journal of Haematology, 146, 686-689. https://doi.org/10.1111/j.1365-2141.2009.07815.x |
| [26] | Bastian, L., Schroeder, M.P., Eckert, C., Schlee, C., Tanchez, J.O., Kämpf, S., et al. (2019) PAX5 Biallelic Genomic Alterations Define a Novel Subgroup of B-Cell Precursor Acute Lymphoblastic Leukemia. Leukemia, 33, 1895-1909. https://doi.org/10.1038/s41375-019-0430-z |
| [27] | Nebral, K., Denk, D., Attarbaschi, A., König, M., Mann, G., Haas, O.A., et al. (2008) Incidence and Diversity of PAX5 Fusion Genes in Childhood Acute Lymphoblastic Leukemia. Leukemia, 23, 134-143. https://doi.org/10.1038/leu.2008.306 |
| [28] | Kwiatkowski, B.A., Zielinska-Kwiatkowska, A.G., Bauer, T.R. and Hickstein, D.D. (2000) The ETS Family Member Tel Antagonizes the Fli-1 Phenotype in Hematopoietic Cells. Blood Cells, Molecules, and Diseases, 26, 84-90. https://doi.org/10.1006/bcmd.2000.0282 |
| [29] | Coffer, P.J. and Burgering, B.M.T. (2004) Forkhead-Box Transcription Factors and Their Role in the Immune System. Nature Reviews Immunology, 4, 889-899. https://doi.org/10.1038/nri1488 |
| [30] | Katoh, M. and Katoh, M. (2004) Human FOX Gene Family (Review). International Journal of Oncology, 25, 1495-1500. https://doi.org/10.3892/ijo.25.5.1495 |
| [31] | Gray, W.R., Sandberg, L.B. and Foster, J.A. (1973) Molecular Model for Elastin Structure and Function. Nature, 246, 461-466. https://doi.org/10.1038/246461a0 |
| [32] | Bousquet, M., Broccardo, C., Quelen, C., Meggetto, F., Kuhlein, E., Delsol, G., et al. (2006) A Novel PAX5-ELN Fusion Protein Identified in B-Cell Acute Lymphoblastic Leukemia Acts as a Dominant Negative on Wild-Type PAX5. Blood, 109, 3417-3423. https://doi.org/10.1182/blood-2006-05-025221 |
| [33] | Jamrog, L., Chemin, G., Fregona, V., Coster, L., Pasquet, M., Oudinet, C., et al. (2018) PAX5-ELN Oncoprotein Promotes Multistep B-Cell Acute Lymphoblastic Leukemia in Mice. Proceedings of the National Academy of Sciences, 115, 10357-10362. https://doi.org/10.1073/pnas.1721678115 |
| [34] | Kurahashi, S., Hayakawa, F., Miyata, Y., Yasuda, T., Minami, Y., Tsuzuki, S., et al. (2011) PAX5-PML Acts as a Dual Dominant-Negative Form of Both PAX5 and PML. Oncogene, 30, 1822-1830. https://doi.org/10.1038/onc.2010.554 |
| [35] | Zhong, S., Salomoni, P., Ronchetti, S., Guo, A., Ruggero, D. and Pandolfi, P.P. (2000) Promyelocytic Leukemia Protein (PML) and Daxx Participate in a Novel Nuclear Pathway for Apoptosis. The Journal of Experimental Medicine, 191, 631-640. https://doi.org/10.1084/jem.191.4.631 |
| [36] | Liu, G.J., Cimmino, L., Jude, J.G., Hu, Y., Witkowski, M.T., McKenzie, M.D., et al. (2014) PAX5 Loss Imposes a Reversible Differentiation Block in B-Progenitor Acute Lymphoblastic Leukemia. Genes & Development, 28, 1337-1350. https://doi.org/10.1101/gad.240416.114 |
| [37] | Hart, M.R., Anderson, D.J., Porter, C.C., Neff, T., Levin, M. and Horwitz, M.S. (2018) Activating PAX Gene Family Paralogs to Complement PAX5 Leukemia Driver Mutations. PLOS Genetics, 14, e1007642. https://doi.org/10.1371/journal.pgen.1007642 |
| [38] | Jia, Z. and Gu, Z. (2022) PAX5 Alterations in B-Cell Acute Lymphoblastic Leukemia. Frontiers in Oncology, 12, Article 1023606. https://doi.org/10.3389/fonc.2022.1023606 |
| [39] | Iacobucci, I., Kimura, S. and Mullighan, C.G. (2021) Biologic and Therapeutic Implications of Genomic Alterations in Acute Lymphoblastic Leukemia. Journal of Clinical Medicine, 10, Article No. 3792. https://doi.org/10.3390/jcm10173792 |
