Molecular hallmarks of adult T cell leukemia

Abstract

The molecular hallmarks of adult T cell leukemia (ATL) comprise outstanding deregulations of signaling pathways that control the cell cycle, resistance to apoptosis, and proliferation of leukemic cells, all of which have been identified by early excellent studies. Nevertheless, we are now confronted the therapeutic difficulties of ATL that is a most aggressive T cell leukemia/lymphoma. Using next-generation strategies, emerging molecular characteristics such as specific surface markers and an additional catalog of signals affecting the fate of leukemic cells have been added to the molecular hallmarks that constitute an organizing principle for rationalizing the complexities of ATL. Although human T cell leukemia virus type 1 is undoubtedly involved in ATL leukemogenesis, most leukemic cells do not express the viral protein Tax. Instead, cellular gene expression changes dominate homeostasis disorders of infected cells and characteristics of ATL. In this review, we summarize the state of the art of ATL molecular pathology, which supports the biological properties of leukemic cells. In addition, we discuss the recent discovery of two molecular hallmarks of potential generality; an abnormal microRNA pattern and epigenetic reprogramming, which strongly involve the imbalance of the molecular network of lymphocytes. Global analyses of ATL have revealed the functional impact of crosstalk between multifunctional pathways. Clinical and biological studies on signaling inhibitory agents have also revealed novel oncogenic drivers that can be targeted in future. ATL cells, by deregulation of such pathways and their interconnections, may become masters of their own destinies. Recognizing and understanding of the widespread molecular applicability of these concepts will increasingly affect the development of novel strategies for treating ATL.

Keywords: ATL; HTLV-1; epigenetics; genome; miRNA; signal transduction.

Figure 1

Transition from HTLV-1-infected cell to transformed leukemic cell. In early and latent clinical phases, the HTLV-1 Tax and HBZ mainly act as driving forces for the molecular hallmarks of infected cells. After a long-term latency, leukemic cells have acquired genetic and epigenetic abnormalities, which lead to deregulations of gene expression pattern, cell cycling, signaling activation, and miRNA expression. These molecular changes consequently induce cellular hallmark capabilities of ATL such as chronic proliferation, apoptotic resistance, multiple organ invasion, and drug resistance.

Figure 2

Acquired molecular hallmarks of ATL. From the beginning of ATL discovery, indicated molecular hallmarks have been suggested. Hierarchical regulation of the gene expression has been expected. Abnormal expressions of these cytokines and receptors as well as various proteins that act as anti-apoptotic factors or proliferation agents are responsible for the malignant phenotypes as hallmark capabilities.

Figure 3

NF-κB signaling pathway in ATL. Compared to normal T cell, HTLV-1-infected cell shows intense activity of NF-κB pathway through the Tax interactome. In contrast, leukemic cell sustains strong NF-κB activity without Tax by acquisition of miR-31-dependent NIK expression. Activation of the non-canonical pathway ultimately joins canonical pathway, resulting in transactivation of numerous target genes important for cell survival, cytokine production, and invasiveness.

Figure 4

Emerging molecular hallmarks, microRNA deregulation and epigenetic reprogramming. An increasing body of research suggests that two additional molecular hallmarks are involved in the pathogenesis of ATL. In addition to the genomic abnormality, epigenetic imbalance widely governs the downstream molecular capabilities. Deregulation of the cellular miRNA levels directly influence hundreds of genes expression. Importantly, cross talking among each category can attain more complex gene regulatory network that is indispensable for exercise of various functions at appropriate timing.

Figure 5

Conceptual illustration of the molecular hallmarks of ATL. This illustration encompasses the six molecular hallmarks of ATL. These organized principles provide characteristics of ATL itself. Because they may be directly associated with the clinical traits of ATL, targeting the one outstanding hallmark or co-targeting of multiple molecular hallmarks in mechanism-guided combinations will result in more effective and durable therapies for aggressive ATL.