Particularly in childhood BCP-ALL, chromosomal abnormalities are important for risk stratification for treatment. The most well-known is the translocation between chromosomes 9 and 22, t(9;22)(q34;q11), otherwise known as the Philadelphia chromosome (Ph), which is the hallmark chromosomal change of chronic myeloid leukemia (Fig. 3A). The translocation gives rise to the BCR-ABL1 fusion with constitutive activation of the tyrosine kinase, BCR-ABL1. The translocation accounts for approximately 2% of BCP-ALL in children and has been associated with a dismal outcome. More recently, treatment with the tyrosine kinase inhibitor imatinib has significantly increased disease-free survival, although it is as yet too early to know if this result will translate into improvements in overall survival.⁷ Trials are in progress to determine whether the new-generation tyrosine kinases, for example dasatinib and nilotinib, can further improve outcome.

Fig. 3 Partial karyotypes from patients with (A) t(9;22)(q34;q11) or the Philadelphia chromosome, (B) t(4;11)(q21;q23), and (C) t(1;19)(q23;p13.3). The chromosomes are numbered underneath each pair, and within each pair the abnormal chromosome is on the right hand side.

Chromosomal abnormalities involving the chromosomal band 11q23, resulting in rearrangements of the MLL gene, account for approximately 2% of childhood BCP-ALL. The translocation, t(4;11)(q21;q23) giving rise to the MLL-AFF1 fusion (previously known as MLL-AF4), is the most common (Fig. 3B). However, more than 80 MLL partners have been reported, with more than 50 of them characterized at the molecular level.⁸ Childhood BCP-ALL patients with t(4;11) have also been classified as high-risk, although this statistic is currently under review because the outcome seems to be age-dependent.⁵

Among patients with TCF3 rearrangements, those with t(1;19)(q23;p13.3)/TCF3-PBX1 fusion (Fig. 3C) were originally regarded as high-risk on some treatment protocols. However, on modern therapy they are classified as standard risk.⁹ In contrast, the rare variant, t(17;19)(q22;p13)/HLF-TCF3 fusion, has a dismal outcome on all therapies.¹⁰ Thus, accurate identification is important for appropriate risk stratification.

Near-haploidy (24–29 chromosomes) and low hypodiploidy (31–39 chromosomes) are rare abnormalities comprising less than 1% each of childhood BCP-ALL. These abnormalities are associated with a poor treatment response, and patients who have them are stratified as high-risk. The abnormalities represent numerical chromosomal changes in ploidy level characterized by the gain of specific chromosomes onto the haploid chromosome set. In the majority of patients, a population of cells with an exact doubling of this chromosome number is present, producing tetrasomies of the gained chromosomes.^11,12 The doubling of a near-haploid population results in a karyotype with over 50 chromosomes, which is easily mistaken for high hyperdiploidy (see high hyperdiploidy section below). The presence of tetrasomies rather than trisomies of the gained chromosomes distinguishes near-haploid doubling from the classical form of high hyperdiploidy. It is important that these differences are identified because of the poor outcome of the near-haploid doubling compared with the good prognosis associated with high hyperdiploidy.

Translocations involving the immunoglobulin heavy chain locus, IGH@, at 14q32 with a range of partner genes are emerging as a significant subgroup in childhood BCP-ALL.¹³–¹⁶ The partners include five of the CEBP gene family members¹³ and the cytokine receptors: EPOR and CRLF2.^15,16 The latter is a cryptic translocation involving IGH@ and the CRLF2 gene, which is located within the pseudoautosomal region (PAR1) of both sex chromosomes, t(X;14)(p22;q32) or t(Y;14)(p11;q32).¹⁶ All IGH@ translocations occur more frequently in older children and adolescents and, although numbers are small, these translocations seem to have an inferior outcome.

The cytogenetic subgroup, intrachromosomal amplification of chromosome 21 (iAMP21), was identified during routine screening for the presence of the ETV6-RUNX1 fusion by fluorescence in situ hybridization (FISH).^17,18 Patients are negative for the ETV6-RUNX1 fusion but show multiple copies of RUNX1 (3 or more additional signals). In metaphase, multiple signals are seen in tandem duplication along an abnormal chromosome 21.¹⁹ In interphase, the signals are clustered together. Cytogenetics, FISH, and genomic approaches have shown that the morphology of the abnormal chromosome 21 is highly variable between patients (Fig. 4). The commonly amplified region always includes the RUNX1 gene.¹⁹–²¹ More recent studies have confirmed that iAMP21 is a primary genetic change and that the mechanisms leading to instability of the abnormal chromosome 21 are inherent within the chromosome structure.²²

Fig. 4 Cytogenetics and array-based comparative genomic hybridization (aCGH) from different iAMP21 patients indicating the variability of the abnormal chromosome 21. (A) Partial karyotypes of 3 pairs of chromosomes 21from 3 different patients with iAMP21. Within each pair the normal chromosome 21 is on the left and the abnormal iAMP21 chromosome on the right. (B) Three aCGH profiles of iAMP21from 3 different patients showing the variable copy number gain and loss along chromosome 21.

iAMP21 was originally described as poor risk,²³ although the outcome has since been shown to be protocol-dependent.²⁴ Thus its accurate detection is important in order to guide therapy.

A significant structural abnormality is the cryptic translocation, t(12;21)(p13;q22)/ETV6-RUNX1 fusion (Fig. 5). This abnormality occurs in approximately 25% of younger children with BCP-ALL.²⁵ These patients have an extremely good prognosis.

Fig. 5 A metaphase showing the t(12;21)(p13;q22)/ETV6-RUNX1 fusion. The chromosomes are counterstained with DAPI (blue) There is one red signal indicating the normal copy of RUNX1 on the normal chromosome 21 (red arrow), a green signal indicating the normal copy of ETV6 on the normal chromosome 12 (green arrow), and a yellow signal indicating the presence of the ETV6-RUNX1 fusion on the derived chromosome 21 (yellow arrow). The second red signal (pale blue arrow) indicates part of the RUNX1 signal on the derived chromosome 12.

High hyperdiploidy (51–65 chromosomes) is an important numerical abnormality.²⁶ It accounts for approximately 30% of childhood BCP-ALL and is characterized by the gain of specific chromosomes. High hyperdiploidy is also associated with an excellent outcome in children. It is largely unknown why both abnormalities are linked to a good prognosis. The reasons may be in part age-related because, overall, younger children have the best treatment response, and these abnormalities occur predominantly in younger children.