Genomic characterization implicates iAMP21 as a likely primary genetic event in childhood B-cell precursor acute lymphoblastic leukemia

Abstract

Intrachromosomal amplification of chromosome 21 (iAMP21) defines a distinct subgroup of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) that has a dismal outcome when treated with standard therapy. For improved diagnosis and risk stratification, the initiating genetic events need to be elucidated. To investigate the genetic basis of BCP-ALL, genomes of 94 iAMP21 patients were interrogated by arrays, FISH, and multiplex ligation-dependent probe amplification. Most copy number alterations targeted chromosome 21, reinforcing the complexity of this chromosome. The common region of amplification on chromosome 21 was refined to a 5.1-mb region that included RUNX1, miR-802, and genes mapping to the Down syndrome critical region. Recurrent abnormalities affecting genes in key pathways were identified: IKZF1 (22%), CDKN2A/B (17%), PAX5 (8%), ETV6 (19%), and RB1 (37%). Investigation of clonal architecture provided evidence that these abnormalities, and P2RY8-CRLF2, were secondary to chromosome 21 rearrangements. Patient outcome was uniformly poor with standard therapy irrespective of the presence or absence of these changes. This study has provided evidence that chromosome 21 instability is the only anomaly among those so far investigated that is common to all iAMP21 patients, and therefore the initiating event is likely to be found among the complex structural rearrangements of this abnormal chromosome.

Blood Spotlight on iAMP21 acute lymphoblastic leukemia (ALL), a high-risk pediatric disease

“…Rare cases have been seen in which iAMP21 occurs in association with other established chromosomal changes, including high hyperdiploidy, BCR-ABL1, or ETV6-RUNX1 4-6 ; otherwise, it has been confirmed to be a primary cytogenetic change, which remains constant in structure between diagnosis and relapse. 7 Similar abnormalities of chromosome 21 have been rarely reported in acute myeloid leukemia and myelodysplastic syndromes, usually in association with complex karyotypes. 8,9 However, the chromosomal regions involved in such cases appear to be different.…”

“…7,10,11 However, in spite of the differences in their genomic profiles, consistent characteristics exist among iAMP21 patients. These features include a common region of highest-level amplification spanning 5.1 Mb of chromosome 21 from 32.8 to 37.9 Mb, within which the RUNX1 gene is located, combined with the lowestlevel copy number distal of this region to the telomere 7 ( Figure 1).…”

“…These include gain of chromosomes X, 10, or 14; or monosomy 7/deletion of 7q; deletions of 11q, including the ATM and MLL genes P2RY8-CRLF2; and deletions of ETV6 and RB1. 4,7,16 As the Down syndrome-critical region on chromosome 21 overlaps with the common region of amplification in iAMP21, coupled with the observation that Down syndrome ALL patients also have a high incidence of gain of chromosome X 17 and P2RY8-CRLF2, 18 it was speculated that iAMP21 ALL may be related to Down syndrome ALL. If this is so, then the relationship is difficult to discern, as iAMP21 has been seen in only a single Down syndrome ALL patient to date.…”

“…11 In addition, no mutations of RUNX1 coding exons, and specifically those within the Runt domain (exons 3, 4, and 5), have been found. 7,14,15 With good reason, RUNX1 is a strong candidate for a driver of the leukemic process in iAMP21 patients, but in the absence of evidence, other genes within the amplified region and or rearranged within the abnormal chromosome 21 have equal opportunity.…”

Routine Cytogenetic Analysis of Chromosome Abnormalities in Acute Lymphoblastic Leukemia

“…ETV6-RUNX1 dual fusion probe). However, there is no evidence that RUNX1 gene is involved [30]. Patients with iAMP21 have a high risk of relapse and require more intensive therapy [31].…”