How advanced are we in targeting novel subtypes of ALL?

Abstract

Despite high cure rates in children, acute lymphoblastic leukemia (ALL) remains a leading cause of cancer death in the young, and the likelihood of treatment failure increases with age. With the exception of tyrosine kinase inhibitors, there have been few advances in repurposing or developing new therapeutic approaches tailored to vulnerabilities of ALL subtypes or individual cases. Large-scale genome profiling studies conducted over the last decade promise to improve ALL outcomes by refining risk stratification and modulation of therapeutic intensity, and by identifying new targets and pathways for immunotherapy. Many of these approaches have been validated in preclinical models and now merit testing in clinical trials. This review discusses the advances in our understanding of the genomic taxonomy and ontogeny of B-progenitor ALL, with an emphasis on those discoveries of clinical importance.

Keywords: ALL; ALL subtype; Acute lymphoblastic leukemia; B-ALL; B-progenitor ALL; DUX4; ETV6-RUNX1; Genome profiling; Hypodiploid; IGH; IKZF1; MEF2D; NUTM1; PAX5; Ph-like; Taxonomy; ZNF384.

Figure 1.

(A) Major B-ALL subtypes based on gene expression profiling of 1988 cases. (B) Distribution of B-ALL subtypes within each age group. Subtypes are grouped as gross chromosomal abnormalities (aneuploidy or copy number gain), transcription factor (TF) rearrangement, other TF-driven, kinase-driven, and all others [10].

Figure 2.

Kinase alterations and signaling pathways dysregulated in Ph-like ALL. The majority of kinase and cytokine receptor alterations converge on two pathways that activate JAK-family member signaling or ABL-signaling. Alterations that activate JAK-STAT signaling can be targeted with JAK and PI3K inhibitors. ABL-class alterations can be targeted with ABL-inhibitors such as dasatinib. Other kinase alterations and those that activate Ras signaling can be targeted with specific inhibitors including those that inactivate TRK, FLT3, FGFR1, and MEK for the MAPK pathway.