f4655a8bec356e39dad408b09b8e48be pmc_33435487.pdf e91df40af2bf9fc4d8d7d8df8bb79226292b30bd pmc_33435487.pdf 3d2d24f64d1ee2d9d8932eb65e9d1379d3c77beb1a4d7e9f8de519e994530ae2 pmc_33435487.pdf Title: The Yin and Yang-Like Clinical Implications of the CDKN2A/ARF/CDKN2B Gene Cluster in Acute Lymphoblastic Leukemia Subject: Acute lymphoblastic leukemia (ALL) is a malignant clonal expansion of lymphoid hematopoietic precursors that exhibit developmental arrest at varying stages of differentiation. Similar to what occurs in solid cancers, transformation of normal hematopoietic precursors is governed by a multistep oncogenic process that drives initiation, clonal expansion and metastasis. In this process, alterations in genes encoding proteins that govern processes such as cell proliferation, differentiation, and growth provide us with some of the clearest mechanistic insights into how and why cancer arises. In such a scenario, deletions in the 9p21.3 cluster involving CDKN2A/ARF/CDKN2B genes arise as one of the oncogenic hallmarks of ALL. Deletions in this region are the most frequent structural alteration in T-cell acute lymphoblastic leukemia (T-ALL) and account for roughly 30% of copy number alterations found in B-cell-precursor acute lymphoblastic leukemia (BCP-ALL). Here, we review the literature concerning the involvement of the CDKN2A/B genes as a prognosis marker of good or bad response in the two ALL subtypes (BCP-ALL and T-ALL). We compare frequencies observed in studies performed on several ALL cohorts (adult and child), which mainly consider genetic data produced by genomic techniques. We also summarize what we have learned from mouse models designed to evaluate the functional involvement of the gene cluster in ALL development and in relapse/resistance to treatment. Finally, we examine the range of possibilities for targeting the abnormal function of the protein-coding genes of this cluster and their potential to act as anti-leukemic agents in patients. Keywords: acute lymphoblastic leukemia; del(9p21.3); prognosis; leukemogenesis; treatment Author: Celia González-Gil, Jordi Ribera, Josep Maria Ribera and Eulàlia Genescà Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Mon Jan 11 04:06:39 2021 CET ModDate: Mon Jan 11 04:12:01 2021 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 27 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 675098 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- OHKNFJ+VnURWPalladioL Type 1 Custom yes yes no 10 0 SXDTXF+URWPalladioL-Ital Type 1 Custom yes yes no 15 0 UXJOUD+URWPalladioL-Bold Type 1 Custom yes yes no 20 0 MITVVS+URWPalladioL-BoldItal Type 1 Custom yes yes no 24 0 TSBQZN+URWPalladioL-Roma Type 1 Custom yes yes no 28 0 AZUTVD+VnURWPalladioL-Bold Type 1 Custom yes yes no 32 0 KONDUX+EuphemiaUCAS-Bold Type 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SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 734 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: Genetic and Epigenetic View of the CDKN2A/B Gene Cluster in ALL Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Children: Item: Title: CDKN2A/B Gene Cluster Organization and Transcripts Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: 9p21.3 Deletion in ALL Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Children: Item: Title: Methods to Detect the Alteration and Possible Origin Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Item: Title: del(9p21.3) in BCP-ALL Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: del(9p21.3) in T-ALL Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: Epigenetic Modifications at the CDKN2A/B Gene Promoter (T-ALL and BCP-ALL) Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: Germline Predisposition Variants in the CDKN2A/B Gene Cluster (T-ALL and BCP-ALL) Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Item: Title: Clinical Impact of CDKN2A/B Alterations in ALL Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@a38d7a3 Children: Item: Title: Clinical Implications of Deletions in BCP-ALL Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77f99a05 Item: Title: Clinical Implications of Deletions in T-ALL Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@63440df3 Item: Title: Clinical Impact of Epigenetic Modifications (BCP-ALL and T-ALL) Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@3aeaafa6 Item: Title: Functional Implications of the CDKN2A/B Locus in ALL Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@76a3e297 Children: Item: Title: Role of INK4a/ARF Proteins in Leukemogenesis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4d3167f4 Item: Title: Role of the INK4a/ARF Proteins in Genomic Instability Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@ed9d034 Item: Title: Consequences of Germline Mutations Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@6121c9d6 Item: Title: Implications of the CDKN2A/B Gene Cluster for Treatment Resistance/Relapse Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@87f383f Item: Title: Therapeutic Approaches to Targeting the INK4 Tumor-Suppressor Protein Family Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4eb7f003 Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@eafc191 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@612fc6eb Info: Title: The Yin and Yang-Like Clinical Implications of the CDKN2A/ARF/CDKN2B Gene Cluster in Acute Lymphoblastic Leukemia Author: Celia González-Gil, Jordi Ribera, Josep Maria Ribera and Eulàlia Genescà Subject: Acute lymphoblastic leukemia (ALL) is a malignant clonal expansion of lymphoid hematopoietic precursors that exhibit developmental arrest at varying stages of differentiation. Similar to what occurs in solid cancers, transformation of normal hematopoietic precursors is governed by a multistep oncogenic process that drives initiation, clonal expansion and metastasis. In this process, alterations in genes encoding proteins that govern processes such as cell proliferation, differentiation, and growth provide us with some of the clearest mechanistic insights into how and why cancer arises. In such a scenario, deletions in the 9p21.3 cluster involving CDKN2A/ARF/CDKN2B genes arise as one of the oncogenic hallmarks of ALL. Deletions in this region are the most frequent structural alteration in T-cell acute lymphoblastic leukemia (T-ALL) and account for roughly 30% of copy number alterations found in B-cell-precursor acute lymphoblastic leukemia (BCP-ALL). Here, we review the literature concerning the involvement of the CDKN2A/B genes as a prognosis marker of good or bad response in the two ALL subtypes (BCP-ALL and T-ALL). We compare frequencies observed in studies performed on several ALL cohorts (adult and child), which mainly consider genetic data produced by genomic techniques. We also summarize what we have learned from mouse models designed to evaluate the functional involvement of the gene cluster in ALL development and in relapse/resistance to treatment. Finally, we examine the range of possibilities for targeting the abnormal function of the protein-coding genes of this cluster and their potential to act as anti-leukemic agents in patients. 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