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Study IDs Targetable Signaling Alterations in Risky ALL Subtype

NEW YORK (GenomeWeb) – In a genomic study of the childhood cancer acute lymphoblastic leukemia, a St. Jude Children's Research Hospital-led team participating in the Pediatric Cancer Genome Project has tracked down recurrent alterations that may be susceptible to tyrosine kinase inhibitors.

As they reported online last night in the New England Journal of Medicine, the researchers did array-based gene expression profiling and/or genotyping on samples from 1,725 children, adolescents, or young adults with a form of ALL known as precursor B-cell ALL that affects white blood cells in the B-cell lineage.

For a subset of those patients with a precursor B-cell ALL sub-type known as Philadelphia chromosome-like ALL, or Ph-like ALL, the team went on to do more detailed transcriptome, genome, and/or exome sequencing analyses on matched tumor and normal samples.

The Ph-like ALL tumors are notable for showing a gene expression pattern that resembles that of ALL cases with the well-known BCR-ABL1 gene fusion, despite lacking the Philadelphia chromosome.

In their new analysis, the investigators determined that Ph-like ALL was somewhat more common in young adults with ALL than in children with the condition, turning up in more than one-quarter of the cases involving individuals over the age of 21 compared to 10 percent of the childhood precursor B-ALL cases.

Moreover, more than 90 percent of the Ph-like ALL samples contained mutations or rearrangements that boosted the activity of kinase signaling pathways, prompting enthusiasm about the potential of treating such cases with tyrosine kinase inhibitors.

The team used whole-genome sequence data for tumor and normal samples from 42 individuals with Ph-like ALL, whole-exome sequence data for a dozen Ph-like ALL tumor and normal pairs, and transcriptome sequence data on 136 Ph-like ALL tumor-normal pairs to narrow in on recurrent alterations in that form of the disease.

They also did transcriptome sequencing on samples from 160 individuals whose precursor B-cell ALL did not show Ph-like expression profiles, along with reverse transcriptase PCR-based tests on samples from a handful of cases that did.

The most common mutations were glitches affecting genes such as FLT3, IL7R, AND SH2B3 genes, though rearrangements affecting a wide range of other kinase coding sequences — including ABL1, ABL2, JAK2, and other genes — turned up in the Ph-like ALL samples as well.

Such findings suggested that some Ph-like ALL tumors may be susceptible to existing treatments such as dasatinib or imatinib that target tyrosine kinase pathways.

Indeed, the study's authors noted that tyrosine kinase inhibitors appeared to be effective against not only Ph-like ALL models in the lab, but also in 11 of the 12 patients with Ph-like ALL from a prospective arm of the study who were treated with tyrosine kinase inhibitors during the study.

Based on such results, they argued in favor of clinical trials aimed at assessing tyrosine kinase inhibitor treatment, in combination with chemotherapy, in Ph-like ALL cases identified through appropriate screening or genomic testing.

"[W]e identified new genomic alterations that converge on a handful of signalling pathways that are vulnerable to treatment with tyrosine kinase inhibitors," senior author Charles Mullighan, a pathology researcher with St. Jude Children's Research Hospital, said in a statement. "The findings lead the way for clinical trials that could help to transform the outlook for patients regardless of age."

"Although our data have highlighted the genetic complexity of Ph-like ALL, this entity can be rapidly identified with a low-density gene expression array," he and his co-authors noted, "and the majority of treatable kinase-activating lesions can be identified with the use of conventional molecular and cytogenetic approaches."

In conjunction with the Children's Oncology Group, the St. Jude team reportedly plans to embark on a clinical trial later in 2014 or in early 2015 that aims to understand the scope of tyrosine kinase inhibitor effectiveness amongst ALL patients enrolled in ongoing COG efforts.

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