Genetic Basis of Acute Lymphoblastic Leukemia

Abstract

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, and despite cure rates exceeding 90% in children, it remains an important cause of morbidity and mortality in children and adults. The past decade has been marked by extraordinary advances into the genetic basis of leukemogenesis and treatment responsiveness in ALL. Both B-cell and T-cell ALL comprise multiple subtypes harboring distinct constellations of somatic structural DNA rearrangements and sequence mutations that commonly perturb lymphoid development, cytokine receptors, kinase and Ras signaling, tumor suppression, and chromatin modification. Recent studies have helped to understand the genetic basis of clonal evolution and relapse and the role of inherited genetic variants in leukemogenesis. Many of these findings are of clinical importance, and ongoing studies implementing clinical sequencing in the management of leukemia are expected to improve diagnosis, monitoring of residual disease, and early detection of relapse and to guide precise therapies. Here, we provide a concise review of genomic studies in ALL and discuss the role of genomic testing in clinical management.

Fig 1.

Age distribution of acute lymphoblastic leukemia (ALL) subtypes. The prevalence of ALL subtypes varies in children with standard-risk (SR) ALL (age 1 to 9 years and WBC count < 50 × 10⁹/L), children with high-risk (HR) ALL (age 10 to 15 years and/or WBC count > 50 × 10⁹/L), and adolescents (age 16 to 20 years), young adults (age 21 to 39 years), adults (age 40 to 59 years), and older adults (age 60 to 86 years) with ALL. Other, B-cell ALL lacking recurrent abnormalities; Ph, Philadelphia chromosome. Data adapted.^-

Fig 2.

Signaling pathways in Philadelphia chromosome (Ph) –like acute lymphoblastic leukemia (ALL). Deregulation of JAK2, ABL, or other (FLT3, NTRK3, BLNK, ABL, PTK2B) signaling pathways in Ph-like ALL is caused by activating mutations (lightning bolts), fusion genes, and/or genomic deletions (X) that are responsible for overexpression of cytokine receptors (eg, CRLF2, IL-7, and EPOR), expression of truncated receptors missing regulatory domains (eg, EPOR), cell delocalization, and constitutive activation of tyrosine kinases. Some downstream signaling pathways are shown. Dashed circles and line represent likely pathways activated by the kinase alterations and amenable to inhibition by kinase inhibitors, respectively. ABLi, Abelson murine leukemia viral oncogene homolog 1 inhibitor; BCL2i, B-cell lymphoma 2 inhibitor; FAKi, focal adhesion kinase inhibitor; FLT3i, Fms-related tyrosine kinase 3 inhibitor; JAKi, JAK inhibitor; MAPK, mitogen-activated protein kinase; MEKi, MAPK/ERK kinase inhibitor; mTORi, mammalian target of rapamycin inhibitor; PI3Ki, phosphoinositide 3-kinase inhibitor; TRKi, tropomyosin receptor kinase inhibitor; Y, tyrosine residue.

Fig 3.

Frequency of Philadelphia chromosome (Ph) –like acute lymphoblastic leukemia (ALL) subtypes across age. Prevalence of CRFL2-rearranged JAK mutant (mut), CRFL2-rearranged JAK wild-type (WT), JAK2 rearrangements (JAK2r), EPOR rearrangements (EPORr), other JAK-STAT alterations, ABL1-class fusions, all other kinase lesions, and unknown subtype in children, young adults, adults, and older adults. Data adapted.^,,

Fig 4.

Mechanism of leukemogenesis mediated by DUX4 and ERG deregulation. DUX4 rearrangements result in profound transcriptional deregulation of ERG and expression of a novel ERG isoform, ERGalt, and frequent RAG-mediated ERG deletions. ERGalt uses a noncanonical first exon whose transcription is initiated by DUX4 binding. It inhibits wild-type (WT) ERG transcriptional activity and is proleukemogenic.