Advances in B-cell Precursor Acute Lymphoblastic Leukemia Genomics

Abstract

In childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL), cytogenetic abnormalities remain important diagnostic and prognostic tools. A number of well-established abnormalities are routinely used in risk stratification for treatment. These include high hyperdiploidy and ETV6-RUNX1 fusion, classified as good risk, while Philadelphia chromosome (Ph) positive ALL and rearrangements of the KMT2A (MLL) gene define poor risk. A poor risk subgroup of intrachromosomal amplification of chromosome 21 (iAMP21-ALL) has been described, in which intensification of therapy has greatly improved outcome. Until recently, no consistent molecular features were defined in around 30% of BCP-ALL (known as B-other-ALL). Recent studies are classifying them into distinct subgroups, some with clear potential for novel therapeutic approaches. For example, in 1 poor risk subtype, known as Ph-like/BCR-ABL1-like ALL, approximately 10% have rearrangements of ABL-class tyrosine kinases: including ABL1, ABL2, PDGFRB, PDGFRA, and CSF1R. Notably, they show a poor response to standard chemotherapy, while they respond to treatment with tyrosine kinase inhibitors, such as imatinib. In other Ph-like-ALL patients, deregulation of the cytokine receptor, CRLF2, and JAK2 rearrangements lead to activation of the JAK-STAT signaling pathway, implicating a specific role for JAK inhibitors in their treatment. Other novel subgroups within B-other-ALL are defined by the IGH-DUX4 translocation, related to deletions of the ERG gene and a good outcome, while fusions involving ZNF384, MEF2D, and intragenic PAX5 amplification (PAX5 ^AMP) are linked to a poor outcome. Continued genetic screening will eventually lead to complete genomic classification of BCP-ALL and define more molecular targets for less toxic therapies.

Figure 1

Pie chart showing the frequency of the major cytogenetic subgroups in BCP-ALL: good risk cytogenetic groups are shown in blue and the poor risk groups in orange. Green indicates intermediate risk. BCP-ALL = B-cell precursor acute lymphoblastic leukemia.

Figure 2

iAMP21-ALL. (A) The chromosome morphology of each iAMP21 chromosome, as seen by standard cytogenetics, is different, as illustrated in the 4 pairs of chromosomes 21 from 4 different iAMP21-ALL patients showing the variable morphology of the abnormal chromosome 21 on the right of each pair. (B) Diagrammatic representation of the expected normal FISH signal pattern using a probe for ETV6 (green) and RUNX1 (red), (i) on metaphase chromosomes 12 and 21, respectively, and (ii) in interphase. The expected abnormal signal pattern of iAMP21-ALL is shown in (iii) by multiple copies of RUNX1 (red) on the iAMP21 chromosome, and in (iv) as clustered red signals in interphase. (C) An example of a characteristic copy number profile of chromosome 21 in iAMP21-ALL, generated from telomeric loss, breakage fusion bridge cycles and chromothripsis, indicated in this profile, by (i) irregular copy number changes, (ii) a common region of amplification that includes RUNX1, and (iii) telomeric loss. FISH = fluorescence in situ hybridization, iAMP21-ALL = intrachromosomal amplification of chromosome 21 acute lymphoblastic leukemia.

Figure 3

The range of genetic abnormalities comprising B-other ALL. The relative distribution of abnormalities is approximated from reports in the literature. Largely the color scheme indicates the associated prognosis, with orange (denoting Ph-like/BCR-ABL1-like) indicating a poor outcome, green indicating a good prognosis, while the remainder are classified as intermediate risk at this time. The proportion of cases currently undefined at the genomic level are indicated in purple. ALL = acute lymphoblastic leukemia.

Figure 4

Summary of iAMP21-ALL along with the novel genetic subtypes reported in B-other ALL and the methods used to identify them. ^†P327-iAMP21-ERG kit includes 46 different probes detecting specific sequences on chromosome 21, including 13 probes for the ERG gene, and 6 probes for RUNX1. ^‡P335-IKZF1-MLPA kit includes probes to detect deletion within the PAR1 region which results in P2RY8-CRLF2 and 6 probes for PAX5 to detect PAX5^AMP∗qPCR and flow cytometry are used to detect over-expression of CRLF2. iAMP21-ALL = intrachromosomal amplification of chromosome 21 acute lymphoblastic leukemia.

Figure 5

Network of gene fusions reported in Ph-like/BCR-ABL1-like ALL. Kinase genes are shown in blue. Gene partners of multiple kinases are shown in red and those so far identified as partner of single kinases are shown in green. ALL = acute lymphoblastic leukemia.