New Challenges in Targeting Signaling Pathways in Acute Lymphoblastic Leukemia by NGS Approaches: An Update

Abstract

The identification and study of genetic alterations involved in various signaling pathways associated with the pathogenesis of acute lymphoblastic leukemia (ALL) and the application of recent next-generation sequencing (NGS) in the identification of these lesions not only broaden our understanding of the involvement of various genetic alterations in the pathogenesis of the disease but also identify new therapeutic targets for future clinical trials. The present review describes the main deletions, amplifications, sequence mutations, epigenetic lesions, and new structural DNA rearrangements detected by NGS in B-ALL and T-ALL and their clinical importance for therapeutic procedures. We reviewed the molecular basis of pathways including transcriptional regulation, lymphoid differentiation and development, TP53 and the cell cycle, RAS signaling, JAK/STAT, NOTCH, PI3K/AKT/mTOR, Wnt/β-catenin signaling, chromatin structure modifiers, and epigenetic regulators. The implementation of NGS strategies has enabled important mutated genes in each pathway, their associations with the genetic subtypes of ALL, and their outcomes, which will be described further. We also discuss classic and new cryptic DNA rearrangements in ALL identified by mRNA-seq strategies. Novel cooperative abnormalities in ALL could be key prognostic and/or predictive biomarkers for selecting the best frontline treatment and for developing therapies after the first relapse or refractory disease.

Significance of Primary Immunodeficiency Disorder (PID)–associated Germline Mutations in Korean patients with ALL

“…In B-ALL, RAS signaling (NRAS, KRAS, PTPN11, FLT3, NF1, et al) and B-cell differentiation and development (PAX5, IKZF1, EBF1, et al) are the most common pathogenic pathways [11,22], and we found a similar distribution of genetic changes in this study. In the adult high-risk cytogenetic group, IKZF1 deletion was the most common alteration (6/12, 50%).…”

“…From a literature review, we selected 500 genes found to be signi cantly mutated in ALL (Additional le 1: Table S1). Our gene panel included [11]: cell cycle and p53 signaling pathway (ATM, CDKN1B, CDKN2A, CDKN2B, RB, TP53, et al), chromatin structure modi ers and epigenetic regulators (ARID1A, BMI1, CHD1, CHD4, CHD9, CREBBP, CTCF, DNMT3A, EED, EP300, EZH2, KDM5C, KDM6A, et al), JAK-STAT signaling pathway (CRLF2, IL2RB, IL7R, JAK1, JAK2, JAK3, PTPN2, SH2B3, STAT3, TYK2, et al…”

The Akt pathway in oncology therapy and beyond (Review)

“…Class IA PI3Ks (PIK3CA, PIK3CB and PIK3CD), are constituted from a p110 catalytic unit and a p85 regulatory one, and are the most important isoforms in cancer studies. PI3Ks are activated by different agents; PI3Kα, β and δ are activated when the extracellular ligands bind to one of the transmembrane glycoproteins with enzymatic activity called receptor tyrosine kinases (RTKs), while PI3Kγ is activated by G-protein-coupled receptors (GPCRs) and by the RAS family of GTPases ( 13 - 15 ).…”

G9a Correlates with VLA-4 Integrin and Influences the Migration of Childhood Acute Lymphoblastic Leukemia Cells

“…Current advances suggest a therapeutic role of epigenetic enzymes, such as DNA methyltransferases and histone deacetylases, with promising results for leukemia patients [ 6 , 24 ]. For instance, it has been suggested that the inhibition of the histone H3K27 demethylase UTX shows promising antitumor effects in T-ALL, while the activity of H3K27 methyltransferase EZH2 acts as tumor suppressor in ALL mouse models [ 25 , 26 ]. Other critical enzymes involved in tumor progression are the H3K9 methyltransferases.…”