Roche NimbleGen CGH Microarrays Further Our Understanding of Childhood Acute Lymphoblastic Leukemia

The most commonly diagnosed form of childhood leukemia, acute lymphoblastic leukemia (ALL), often responds well to biologically-targeted therapeutic treatments, but also carries a 25% risk for relapse. ALL is frequently associated with a chromosomal translocation that involves the specific translocation of gene loci from the short (p) arm of chromosome 12 to chromosome 21 denoted as t(12;21) TEL-AML1 (ETV6-RUNX1). This translocation often results in fusions of the TEL (or ETV6) gene with the AML1 (or RUNX1) gene and is present in 1% of all newborns and at a higher 22% proportion among children with the ALL diagnosis.

Cancer is hypothesized to develop because of the cumulative effects of multiple mutation events or “hits”. In leukemogenesis, this frequently is described as a “two-hit hypothesis”, in which two distinct mutation events are required for the disease to progress. The TEL-AML1 translocation, which has been detected at a high rate among newborns, is considered the first hit in this scenario. A secondary, postnatal mutation seemed to be plausible as a critical rate-limiting event for leukemia. In ALL, the most common subsequent mutation is a partial deletion of chromosome 12p, or del(12p).

To further define the timing and structure of the del(12p) “secondary hit” associated with ALL, Weimels and coworkers (1) analyzed samples from participants in an epidemiologic research study focused on the etiology of childhood leukemia in a 35-county area in California. Roche NimbleGen provided a custom human CGH 385K microarray consisting of 50bp long oligonucletide probes tiled across the 38Mb p-arm of chromosome 12, which enabled the characterization of chromosome deletion breakpoints at sub-kilobase resolution.

Of the ten samples analyzed using NimbleGen CGH arrays, all showed the TEL-AML1 translocation and 9 had a deletion of the second TEL allele by fluorescent in situ hybridization (FISH) analysis. The higher resolution NimbleGen CGH array revealed interstitial deletions within the chromosome 12 p-arm in 4 samples, and single breakpoints with deletion of the remainder of the chromosome arm in 5 samples. In addition, array CGH revealed an unexpected association of del(12p) rearrangements with SINE and LINE retrotransposons in the human genome. The results of Weimels’ study provides additional support for the for "two-hit hypothesis", stating that the TEL-AML1 translocation is a prenatal occurrence and del(12p) is a postnatal, secondary event in more mature cells with a structure that suggests the involvement of retrotransposon instability.

Gerd Maass, CEO of Roche NimbleGen stated, “The use of NimbleGen arrays in hematological studies like these clearly demonstrates the enormous potential of microarrays to rapidly screen and discern significant differences among populations and individuals at the molecular level. Each chromosomal gain or loss, genetic abnormality, or other mutagenic event contributes to the full context of a disease pathway, regardless of whether it’s the first, second, or twentieth cumulative hit. Roche NimbleGen is committed to providing researchers with these essential laboratory tools to help discover the origins and causes of such diseases.”