T-Cell Acute Lymphoblastic Leukemia: Biomarkers and Their Clinical Usefulness

Abstract

T-cell acute lymphoblastic leukemias (T-ALL) are immature lymphoid tumors localizing in the bone marrow, mediastinum, central nervous system, and lymphoid organs. They account for 10–15% of pediatric and about 25% of adult acute lymphoblastic leukemia (ALL) cases. It is a widely heterogeneous disease that is caused by the co-occurrence of multiple genetic abnormalities, which are acquired over time, and once accumulated, lead to full-blown leukemia. Recurrently affected genes deregulate pivotal cell processes, such as cycling (CDKN1B, RB1, TP53), signaling transduction (RAS pathway, IL7R/JAK/STAT, PI3K/AKT), epigenetics (PRC2 members, PHF6), and protein translation (RPL10, CNOT3). A remarkable role is played by NOTCH1 and CDKN2A, as they are altered in more than half of the cases. The activation of the NOTCH1 signaling affects thymocyte specification and development, while CDKN2A haploinsufficiency/inactivation, promotes cell cycle progression. Among recurrently involved oncogenes, a major role is exerted by T-cell-specific transcription factors, whose deregulated expression interferes with normal thymocyte development and causes a stage-specific differentiation arrest. Hence, TAL and/or LMO deregulation is typical of T-ALL with a mature phenotype (sCD3 positive) that of TLX1, NKX2-1, or TLX3, of cortical T-ALL (CD1a positive); HOXA and MEF2C are instead over-expressed in subsets of Early T-cell Precursor (ETP; immature phenotype) and early T-ALL. Among immature T-ALL, genomic alterations, that cause BCL11B transcriptional deregulation, identify a specific genetic subgroup. Although comprehensive cytogenetic and molecular studies have shed light on the genetic background of T-ALL, biomarkers are not currently adopted in the diagnostic workup of T-ALL, and only a limited number of studies have assessed their clinical implications. In this review, we will focus on recurrent T-ALL abnormalities that define specific leukemogenic pathways and on oncogenes/oncosuppressors that can serve as diagnostic biomarkers. Moreover, we will discuss how the complex genomic profile of T-ALL can be used to address and test innovative/targeted therapeutic options.

Abnormal GRHL2 Methylation Confers Malignant Progression to Acute Leukemia

“…Epigenetics indicates the alterations of gene expression levels mediated by nongene sequence changes. It is involved in cell differentiation, maintenance of cell differentiation state, tumorigenesis, and cell senescence, mainly through DNA methylation, histone acetylation, and RNA-related silencing [ 6 ].…”

Prospective quantitative gene expression analysis of kallikrein-related peptidase KLK10 as a diagnostic biomarker for childhood acute lymphoblastic leukemia

“…However, only four T-ALL patients were considered in this research. This subtype is less prevalent, and it affects adults more than children ( Bardelli et al, 2021 ).…”

Genome-wide identification of alternative splicing associated with histone deacetylase inhibitor in cutaneous T-cell lymphomas

“…CNN1 regulates DKK1/Wnt/β-catenin/c-Myc signaling pathway by activating the tissue inhibitors of metalloproteinases, and blocking the proliferation and metastasis of lung squamous carcinoma cells ( Liu et al, 2021 ). Exome sequencing revealed mutations in CNOT3 and the ribosomal genes RPL5 and RPL10 in acute lymphoblastic leukemia ( De Keersmaecker et al, 2013 ; Bardelli et al, 2021 ). Furthermore, DQX1 is reportedly associated with the prognosis of renal cell carcinoma ( Qin et al, 2021 ).…”