Unraveling of molecular changes in acute lymphoblastic leukemia (ALL) opens new treatment options

The molecular characteristics of acute lymphoblastic leukemia (ALL) have been decoded, and these findings were published in Nature Genetics (2015; doi:10.1038/ng.3362) by an international team of European scientists from Berlin, Düsseldorf, Hannover, Heidelberg, Kiel, and Zurich. This paves the way for new therapeutic approaches for the t(17;19) ALL subtype.

ALL is the most common type of cancer in children and some subtypes are currently incurable. The cancer can occur in various forms, differing not only by specific changes in the genetic material of the leukemia cells but also by their response to therapies.

Although intensive research over the last decade has significantly improved the survival rates of children with ALL, a subset of patients remains resistant to treatment. One example is the very aggressive and incurable subtype associated with a t(17;19) chromosomal translocation, which is caused by breakage and aberrant fusion of genetic material in the tumor cells, resulting in the formation of a new oncogenic protein encoded by the genes TCF3 and HLF (TCF3-HLF-positive leukemia cells). Until now, the molecular basis of this phenotype has remained elusive.

The consortium team decoded the genome of the leukemic cells using sophisticated bioinformatics methods. The team found genetic aberrations in addition to the known translocation.

"We are glad that we could contribute to this important project with genomic data analysis of leukemia cells to unravel some of the molecular changes in this disease", said Bodo Lange, MD, CEO of Alacris Theranostics, which is a spin-off of the Max Planck Institute for Molecular Genetics in Berlin, Germany.

With the aim of identifying therapeutic entry points for this incurable form of ALL, the transcriptome of the cancer cells was also analyzed in great detail, enabling identification of the genes active within the leukemic cell.

The so-called expression profile of the cancer cells was deciphered by means of RNAseq. The interplay between the fused TCF3-HLF oncogenic protein, additional DNA changes, and altered gene expression program leads to a re-programming of leukemic cells to an early, stem-cell like developmental stage, although the phenotypic appearance of the cells remains similar.

"This technique provides a quantitative read out of the actual genetic program occurring in the cancer cells, which allowed us to uncover relevant molecular mechanisms cooperating to promote tumorigenesis, and to identify possible druggable targets. These findings could only be achieved through analysis of the messenger RNAs," said Marie-Laure Yaspo, PhD, of the Max Planck Institute.

In tandem, researchers from the team of Jean-Pierre Bourquin (University Children's Hospital, Zürich, Switzerland) transplanted the leukemic cells in mice and established a humanized mouse model, an invaluable tool for testing therapeutic response. The consortium team demonstrated that the mouse engrafted and expanded cells retained most of the genetic features and expression profiles of the original leukemic cells. The cells thus behaved in a similar manner than in the patient, offering an attractive possibility for translational medicine.

The Zurich Group tested close to one hundred drugs, and demonstrated a very positive response of the mouse model TCF3-HLF-positive cells to venetoclax, a drug targeting the protein BCL2, that has already showed efficiency in other type of cancers.

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