The genetics and molecular biology of T-ALL Tiziana Girardi 1,2 , Carmen Vicente 2,3,4 , Jan Cools 2,3,4 , and Kim De Keersmaecker 1,2 1 Department of Oncology, KU Leuven, Leuven, Belgium 2 Leuven Cancer Institute (LKI), Leuven, Belgium 3 VIB Center for the Biology of Disease, Leuven, Belgium 4 Center for Human Genetics, KU Leuven, Leuven, Belgium Abstract T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy caused by the accumulation of genomic lesions that affect the development of T-cells. Since many years, it has been established that deregulated expression of transcription factors, impairment of the CDKN2A/2B cell cycle regulators and hyperactive NOTCH1 signaling play prominent roles in the pathogenesis of this leukemia. In the past decade, systematic screening of T-ALL genomes by high resolution copy number arrays and next- generation sequencing technologies has revealed that T- cell progenitors accumulate additional mutations affecting JAK/STAT signaling, protein translation and epigenetic control, providing novel attractive targets for therapy. In this review, we provide an update on our knowledge on T-ALL pathogenesis, on the opportunities for the introduction of targeted therapy and on the challenges that are still ahead. Introduction The characterization of chromosomal abnormalities, such as 9p deletions resulting in inactivation of CDKN2A (p16) and CDKN2B (p15) and translocations affecting the T-cell receptor genes, have been fundamental in providing initial insights in the genetic defects present in T-ALL. The incorporation of gene expression profiling has provided an additional view on the subgroups present in T-ALL, each characterized by the presence of specific chromosomal aberrations leading to ectopic expression of one particular transcription factor such as TAL1, TLX1, TLX3 or others. Sequencing approaches focusing on candidate oncogenes or more recently genome wide sequencing (exome sequencing, whole genome sequencing or transcriptome sequencing) have identified more than 100 genes that can be mutated in T-ALL. Only two of these genes, NOTCH1 and CDKN2A/2B are mutated in more than 50% of T-ALL cases, and a large variety of genes is mutated at lower frequency Correspondence, Jan Cools: CME, Campus Gasthuisberg O&N4, Herestraat 49 (box 602), 3000 Leuven, Belgium, jan.cools@kuleuven.be, Kim De Keersmaecker: Department of Oncology, Campus Gasthuisberg O&N1, Herestraat 49 (box 603), 3000 Leuven, Belgium. kim.dekeersmaecker@kuleuven.be. Authorship Contributions TG, CV, JC and KDK contributed to data analysis and writing of the manuscript Disclosure of Conflicts of Interest The authors declare no competing financial interests Europe PMC Funders Group Author Manuscript Blood. Author manuscript; available in PMC 2017 March 23. Published in final edited form as: Blood. 2017 March 02; 129(9): 1113–1123. doi:10.1182/blood-2016-10-706465. Europe PMC Funders Author Manuscripts Europe PMC Funders Author Manuscripts