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

Abstract

Intrachromosomal amplification of chromosome 21 (iAMP21) defines a distinct cytogenetic subgroup of childhood B-cell precursor acute lymphoblastic leukemia. Breakage-fusion-bridge cycles followed by chromothripsis and other complex structural rearrangements of chromosome 21 underlie the mechanism giving rise to iAMP21. Patients with iAMP21 are older (median age 9 years), with a low white cell count. They have a high relapse rate when treated as standard risk. Recent studies have shown improved outcome on intensive therapy. Molecular targets for therapy are being sought.

Maternal iAMP21 acute lymphoblastic leukemia detected on prenatal cell-free DNA genetic screening

“…This region of amplification is consistent with that seen in iAMP21 B-cell ALL cases 3,16 and contains several genes implicated in B-ALL pathogenesis, including RUNX1, 17 DYRK1A, 18 ERG, 19 and HMGN1. 20 The specific driver or drivers of leukemogenesis in iAMP21 are not yet clearly defined, but the amplification event is thought to occur via chromothripsis, a phenomenon of extensive genomic rearrangement usually confined to a single chromosome.…”

“…In sum, these genetic findings are consistent with a diagnosis of iAMP21 B-cell ALL (based on the multiple additional RUNX1 copies), a provisional entity in the World Health Organization classification of acute leukemia. [2][3][4] After diagnosis of B-cell ALL, it was recognized that the patient had undergone routine prenatal cfDNA screening (QNatal Advanced, Quest Diagnostics) from a maternal blood sample drawn ;14 weeks prior, at 12 weeks and 2 days of gestation. A complete blood count ;4 weeks prior to cfDNA screening showed mild leukopenia (white blood cell count of 2.9 3 10 9 /L with normal differential) without anemia, thrombocytopenia, or abnormal cells.…”

Progress and Prospects in Pediatric Leukemia

“…12 But internal amplification of RUNX1 (iAMP 21) within the same chromosome, which is found in less than 2% of cases, is associated with a poor prognosis. 13 The Philadelphia (Ph) chromosome, BCR-ABL fusion t(9; 22) (q34; q11) is found in 2-3% of pediatric B-ALL in contrast to a much higher incidence in adult ALL. 11 Ph-positive ALL historically had a poor prognosis with an event-free survival (EFS; Table 1) of up to 34% at 5 years, 14 but the advent of tyrosine kinase inhibitors has remarkably improved outcomes to an EFS of 70% at 5 years, without hematopoietic stem cell transplantation (HSCT).…”

Molecular basis and clinical significance of genetic aberrations in B-cell precursor acute lymphoblastic leukemia

“…iAMP21 is characterized by a gain of at least three copies of a large but variable region on chromosome 21, which always contains RUNX1, and is frequently accompanied with deletion of the subtelomeric regions of chromosome 21 [130,131]. Importantly, iAMP21 has been associated with poor outcome [132].…”