Biologic and Therapeutic Implications of Genomic Alterations in Acute Lymphoblastic Leukemia

Abstract

Acute lymphoblastic leukemia (ALL) is the most successful paradigm of how risk-adapted therapy and detailed understanding of the genetic alterations driving leukemogenesis and therapeutic response may dramatically improve treatment outcomes, with cure rates now exceeding 90% in children. However, ALL still represents a leading cause of cancer-related death in the young, and the outcome for older adolescents and young adults with ALL remains poor. In the past decade, next generation sequencing has enabled critical advances in our understanding of leukemogenesis. These include the identification of risk-associated ALL subtypes (e.g., those with rearrangements of MEF2D, DUX4, NUTM1, ZNF384 and BCL11B; the PAX5 P80R and IKZF1 N159Y mutations; and genomic phenocopies such as Ph-like ALL) and the genomic basis of disease evolution. These advances have been complemented by the development of novel therapeutic approaches, including those that are of mutation-specific, such as tyrosine kinase inhibitors, and those that are mutation-agnostic, including antibody and cellular immunotherapies, and protein degradation strategies such as proteolysis-targeting chimeras. Herein, we review the genetic taxonomy of ALL with a focus on clinical implications and the implementation of genomic diagnostic approaches.

Treatment of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia in Adults

“…The genetic landscape of ALL is heterogeneous and varies with age. Philadelphia-chromosome is the most common cytogenetic abnormality among adult ALL patients, accounting for 25% of cases with incidence increasing to more than 40% in the elderly [ 1 , 2 ]. Philadelphia-chromosome positive (Ph+) ALL is characterized by the presence of reciprocal translocation t(9;22)(q34;q11), leading to BCR-ABL fusion gene encoding BCR-ABL oncoprotein, that has constitutive tyrosine kinase activity and plays a central role in ALL development [ 3 , 4 ].…”

An easy-to-use nomogram predicting overall survival of adult acute lymphoblastic leukemia

“…These hematological parameters may be associated with genetic abnormalities in ALL ( 10 ). Various chromosomal alterations in ALL are important in driving chromosomal gains and losses that may be associated with the target therapy, survival and relapse of the disease ( 5 , 11 , 12 ). Chromosomal abnormalities such as t (4;11) (q21;q23) are associated with poor prognosis ( 13 , 14 ), whereas patients with t(12;21)(p13;q22) translocation have a better survival rate ( 15 , 16 ).…”

“…The clinical significance of the mutated genes is still controversial. However, patients with mutated IKZF1 and PAX5 had poor survivals ( 11 ).…”

Microphysiological Drug-Testing Platform for Identifying Responses to Prodrug Treatment in Primary Leukemia

“…In addition, some cell lines have been reported to be resistant to anticancer molecules 6 , which has further reduced their applicability for drug testing. More recently, the growing clinical interest in genomic profiling of primary leukemia cases has greatly helped to understand the lesions that occur in cancer, especially for pediatric ALL, with implications on treatment identification 7,8 . This improved understanding has led to several functional approaches to develop precision and personalized medicine tools by sequencing and testing primary leukemia cells at single-cell resolution to identify drug response profiles of patients [9][10][11][12][13] .…”