The genetics and molecular biology of T-ALL

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. For 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 of T-ALL pathogenesis, the opportunities for the introduction of targeted therapy, and the challenges that are still ahead.

Figure 1. Deregulation of the JAK-STAT signaling cascade in T-ALL

Representation of the different oncogenic mechanisms that lead to aberrant activation of the IL7 signaling in T-ALL. Interaction of IL7 with the heterodimeric IL7 receptor induces reciprocal JAK1 and JAK3 phosphorylation and subsequent recruitment of STAT5. STAT5 dimerizes and translocates to the nucleus where it induces transcription of the pro-survival factor BCL2. IL7 also activates the RAS-MAPK and PI3K kinase pathways. IL7 signaling can indirectly be enhanced by abnormal NOTCH1 signaling, constitutive expression of ZEB2 or by increased presentation of IL7R on the cell surface of thymocytes due to impaired clathrin-dependent endocytosis caused by DNM2 mutations. Proteins that are mutated in T-ALL are indicated with an asterisk. Promising therapeutic agents targeting the oncogenic IL7-JAK-STAT cascade are indicated in red.

Figure 2. Representation of the cooperation of oncogenic events

The major subclasses of T-ALL are shown based on the expression of the transcription factors TAL1, TLX1, TLX3, HOXA genes, NKX2-1 or LMO2/LYL1. For each subclass, additional genes are shown that are most frequently mutated in that subclass. The PRC2 complex contains EZH2, SUZ12 and EED.