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Review
. 2015 Jun 25;125(26):3977-87.
doi: 10.1182/blood-2015-02-580043. Epub 2015 May 21.

Redefining ALL classification: toward detecting high-risk ALL and implementing precision medicine

Stephen P Hunger  1 , Charles G Mullighan  2
Affiliations
Review

Redefining ALL classification: toward detecting high-risk ALL and implementing precision medicine

Stephen P Hunger et al. Blood. .

Abstract

Acute lymphoblastic leukemia (ALL) is the commonest childhood tumor and remains a leading cause of cancer death in the young. In the last decade, microarray and sequencing analysis of large ALL cohorts has revolutionized our understanding of the genetic basis of this disease. These studies have identified new ALL subtypes, each characterized by constellations of structural and sequence alterations that perturb key cellular pathways, including lymphoid development, cell-cycle regulation, and tumor suppression; cytokine receptor, kinase, and Ras signaling; and chromatin modifications. Several of these pathways, particularly kinase-activating lesions and epigenetic alterations, are logical _targets for new precision medicine therapies. Genomic profiling has also identified important interactions between inherited genetic variants that influence the risk of leukemia development and the somatic genetic alterations that are required to establish the leukemic clone. Moreover, sequential sequencing studies at diagnosis, remission, and relapse have provided important insights into the relationship among genetic variants, clonal heterogeneity, and the risk of relapse. Ongoing studies are extending our understanding of coding and noncoding genetic alterations in B-progenitor and T-lineage ALL and using these insights to inform the development of faithful experimental models to test the efficacy of new treatment approaches.

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Figures

Figure 1
Figure 1
Prevalence of ALL subtypes across age groups. The prevalence of ALL subtypes varies between children with standard-risk ALL (age 1-9 years, white blood cell count <50 × 109/L), children with high-risk ALL (age 10-15 years and/or white blood cell count >50 × 109/L), adolescents (age 16-20 years), and young adults with ALL (age 21-39 years). B-other, B-cell ALL with other subtypes.
Figure 2
Figure 2
Schema for the genetic pathogenesis of B-ALL. Key inherited and somatic genomic variants and their relationship to the development of ALL and treatment failure are shown. Representative alterations are shown.
Figure 3
Figure 3
Frequency of subtypes of Ph-like ALL. Combined prevalence of Ph-like ALL subtypes in children, adolescents, and young adults including CRFL2-rearranged JAK2 mutant (CRLF2r_JAK2 mut) and CRFL2-rearranged JAK2 wild-type (CRFL2r_JAK2 WT), ABL1-class rearrangements (ABL1, ABL2, CSF1R, and PDGFRB), JAK2 and EPOR rearrangements and other mutations in JAK-STAT signaling (FLT3, IL7R, SH2B3, JAK1/3, TYK2, IL2RB, and TSLP), Ras mutations (KRAS, NRAS, NF1, PTPN11, and BRAF), and unknown alterations. Data from Roberts et al. HR, high-risk.
Figure 4
Figure 4
ABL1-class rearrangements in Ph-like ALL. The figure shows each ALL sample as a column, each kinase rearrangement as a green box, and the diverse range of fusion partners in blue. On the right, representative schema of fusion proteins are shown, showing preservation of the kinase domain in the C terminus of the protein and fusion partners uniformly in the 5′ region of the protein, with domains that mediate overexpression of the kinase, cellular mislocalization, and dimerization of the fusion protein. TKD, tyrosine kinase domain.
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