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.

Keywords: T-ALL; genomic profile; molecular-cytogenetic markers.

Figure 1

Schematic representation of genomic mechanisms of gene deregulation in T-ALL. Dotted lines: deletion; *: mutation; E: enhancer.

Figure 2

Distribution of the main genetic subgroups in T-ALL of: (A) adults and (B) children [7,8,9,10].

Figure 3

TAL/LMO genetic subgroup: Frequency of TAL and/or LMO rearrangements [8,9]. * In this group, including all rearrangements of TAL1, 47% of cases are represented by STIL-TAL1 fusions; °TAL1+LMO1, or TAL1+LMO2, or TAL1-LMO3; ^#LMO2 abnormalities are rarely combined with the rearrangement of LYL1; _E, super-enhancer created by mutations of noncoding intergenic sequences [8].

Figure 4

Stages of T-ALL differentiation and distribution of NOTCH1/FBXW7 mutations and CDKN2AB deletions.

Figure 5

Genetic classification of ETP-ALL [7,8,10].

Figure 6

HOXA genetic subgroup: Genes associated with high levels of HOXA expression and frequency of their alterations [8,9].

Figure 7

(A) Available molecular-cytogenetics techniques; (B) Diagnostic algorythm_Personal Experience. CI-FISH (combined interphase-fluorescence in situ hybridization) assay is fully described in La Starza R et al. [8]; CNA, Copy Number Alterations; NGS, Next Generations Sequencing; WGS, Whole Genome Sequencing; WES, Whole Exome Sequencing; RNASeq, RNA sequencing; TS, Targeted Sequencing.