Molecular basis of acute lymphoblastic leukemia

Chapter 5 Molecular basis of acute lymphoblastic leukemia Shunsuke Kimura, Shunsuke Kimura Department of Pathology, Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, TN, USASearch for more papers by this authorCharles G. Mullighan, Charles G. Mullighan Department of Pathology, Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, TN, USASearch for more papers by this author Shunsuke Kimura, Shunsuke Kimura Department of Pathology, Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, TN, USASearch for more papers by this authorCharles G. Mullighan, Charles G. Mullighan Department of Pathology, Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, TN, USASearch for more papers by this author Book Editor(s):Drew Provan, Drew ProvanSearch for more papers by this authorHillard M. Lazarus, Hillard M. LazarusSearch for more papers by this author First published: 08 March 2024 https://doi.org/10.1002/9781394180486.ch5 AboutPDFPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShareShare a linkShare onEmailFacebookTwitterLinkedInRedditWechat Summary Survival rates for pediatric acute lymphoblastic leukemia (ALL) have improved significantly, but adult ALL still poses challenges with lower cure rates. The molecular understanding of ALL has played an important role in risk stratification and treatment optimization. Molecular characterization has identified various subtypes of B-ALL based on genetic alterations. This may allow for tailored therapies that have been successful in certain ALL subtypes, such as BCR::ABL1 -positive ALL, where the addition of tyrosine kinase inhibitors has significantly improved outcomes in both adults and children. Recent advances in high-throughput sequencing technologies have comprehensively characterized ALL subtypes, enabling the identification or definition of leukemia-driving alterations, including fusion oncogenes, non-coding alterations, enhancer retargeting, and even single-point mutations. Furthermore, some genomic alterations ( ZNF -rearranged B-ALL and BCL11B -rearranged T-ALL) transcend the lineages and thus, we now know that diagnosis of these leukemias should be based on genomic alterations regardless of immunophenotype. However, despite the progress in understanding genomic basis, the implementation of high-throughput sequencing technologies in clinical settings is still limited due to cost and lack of standardization of the diagnostic process, and only available for a small number of ongoing clinical trials that test targeted therapies for specific ALL subtypes. In addition, further understanding of ALL biology is still required, including exploration of epigenomics, proteomics, cell of origin, heterogeneity, and microenvironments. While challenges remain in clinical implementation and understanding the full complexity of the disease, these developments pave the way for future improvements in ALL management and outcomes. Further reading Iacobucci , I. , Kimura , S. , and Mullighan , C.G. ( 2021 ). Biologic and therapeutic implications of genomic alterations in acute lymphoblastic leukemia . J. Clin. Med. 10 ( 17 ): 3792 . 10.3390/jcm10173792 CASPubMedWeb of Science®Google Scholar Kimura , S. and Mullighan , C.G. ( 2020 ). Molecular markers in ALL: clinical implications . Best Pract. Res. Clin. Haematol. 33 ( 3 ): 101193 . 10.1016/j.beha.2020.101193 PubMedWeb of Science®Google Scholar Brady , S.W. , Roberts , K.G. , Gu , Z. et al . ( 2022 ). The genomic landscape of pediatric acute lymphoblastic leukemia . Nat. Genet. 54 ( 9 ): 1376 – 1389 . 10.1038/s41588-022-01159-z CASPubMedWeb of Science®Google Scholar Gu , Z. , Churchman , M.L. , Roberts , K.G. et al . ( 2019 ). PAX5-driven subtypes of B-progenitor acute lymphoblastic leukemia . Nat. Genet. 51 ( 2 ): 296 – 307 . 10.1038/s41588-018-0315-5 CASPubMedWeb of Science®Google Scholar Roberts , K.G. , Li , Y. , Payne-Turner , D. et al . ( 2014 ). Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia . N. Engl. J. Med. 371 ( 11 ): 1005 – 1015 . 10.1056/NEJMoa1403088 CASPubMedWeb of Science®Google Scholar Mullighan , C.G. , Goorha , S. , Radtke , I. et al . ( 2007 ). Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia . Nature 446 ( 7137 ): 758 – 764 . 10.1038/nature05690 CASPubMedWeb of Science®Google Scholar Mullighan , C.G. , Miller , C.B. , Radtke , I. et al . ( 2008 ). BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros . Nature 453 ( 7191 ): 110 – 114 . 10.1038/nature06866 CASPubMedWeb of Science®Google Scholar Zhang , J. , Ding , L. , Holmfeldt , L. et al . ( 2012 ). The genetic basis of early T-cell precursor acute lymphoblastic leukaemia . Nature 481 ( 7380 ): 157 – 163 . 10.1038/nature10725 CASPubMedWeb of Science®Google Scholar Liu , Y. , Easton , J. , Shao , Y. et al . ( 2017 ). The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia . Nat. Genet. 49 ( 8 ): 1211 – 1218 . 10.1038/ng.3909 CASPubMedWeb of Science®Google Scholar Mansour , M.R. , Abraham , B.J. , Anders , L. et al . ( 2014 ). Oncogene regulation. An oncogenic super-enhancer formed through somatic mutation of a non-coding intergenic element . Science 346 ( 6215 ): 1373 – 1377 . 10.1126/science.1259037 CASPubMedWeb of Science®Google Scholar Gianni , F. , Belver , L. , and Ferrando , A. ( 2020 ). The genetics and mechanisms of T-cell acute lymphoblastic leukemia . Cold Spring Harb. Perspect. Med. 10 ( 3 ): a035246 . 10.1101/cshperspect.a035246 CASPubMedGoogle Scholar Yui , M.A. and Rothenberg , E.V. ( 2014 ). Developmental gene networks: a triathlon on the course to T cell identity . Nat. Rev. Immunol. 14 ( 8 ): 529 – 545 . 10.1038/nri3702 CASPubMedWeb of Science®Google Scholar Hosokawa , H. and Rothenberg , E.V. ( 2021 ). How transcription factors drive choice of the T cell fate . Nat. Rev. Immunol. 21 ( 3 ): 162 – 176 . 10.1038/s41577-020-00426-6 CASPubMedWeb of Science®Google Scholar Alexander , T.B. , Gu , Z. , Iacobucci , I. et al . ( 2018 ). The genetic basis and cell of origin of mixed phenotype acute leukaemia . Nature 562 ( 7727 ): 373 – 379 . 10.1038/s41586-018-0436-0 CASPubMedWeb of Science®Google Scholar Montefiori , L.E. , Bendig , S. , Gu , Z. et al . ( 2021 ). Enhancer hijacking drives oncogenic BCL11B expression in lineage-ambiguous stem cell leukemia . 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