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.

Identification of fusion genes and characterization of transcriptome features in T-cell acute lymphoblastic leukemia

“…A better understanding of T-ALL in an adult group may allow more rational disease stratification and precision therapy. Over the past three decades, many genetic abnormalities have been found in T-ALL (3)(4)(5). Aberrant expression of genes such as LMO1, LMO2, TAL1, TLX1, TLX3, and other transcription factors (TFs) can be either due to chromosomal rearrangements juxtaposing T-cell receptor (TCR) loci to these genes or due to the recently described somatic mutations in enhancer regions recruiting relevant TFs such as MYB (6,7).…”

Mutational dynamics of early and late relapsed childhood ALL: rapid clonal expansion and long-term dormancy

“…However, we did not observe the recently reported enrichment of mutations in the JAK-STAT pathway in relapsed cALL patients. 13 Alterations of this pathway are common genomic features of Ph-like acute lymphoblastic leukemia (ALL), 36 and although we missed expression data allowing a classification of cases in this particular subgroup, we suspect the observed divergence to rely on a lack of representatives in our cohort. With the rise and fall of numerous mutated clones, epigenetic regulation and MAP kinase-RAS signaling were the 2 most represented (84.2% and 78.9% of mutated patients, respectively) and dynamic signaling pathways.…”

Applications of Flow Cytometric Immunophenotyping in the Diagnosis and Posttreatment Monitoring of B and T Lymphoblastic Leukemia/Lymphoma

“…Despite their genetic heterogeneity , cases of T lymphoblastic leukemia/lymphoma are not yet further subclassified by the WHO on the basis of recurrent genetic abnormalities. The WHO does, however, recognize early T‐cell precursor (ETP) lymphoblastic leukemia, which is distinguished from non‐ETP lymphoblastic leukemia by FCI.…”