Carving a NOTCH in Pediatric
T-ALL Pathogenesis

More and more investigators are suggesting that there appear to be only five main signaling pathways disrupted in malignant transformation: receptor tyrosine kinases, Gli/hedgehog, Notch, TGF beta, and Wnt. Thus far the majority of pathogenetic investigations in hematological malignancies have focused on aberrant or dysregulated signal transduction through tyrosine kinase pathways. Now, investigators from the British Columbia Cancer Agency, the Dana- Farber Cancer Center, and the Brigham and Women’s Hospital have begun to link the NOTCH signaling pathway with human T cell acute lymphoblastic leukemia. Abstract #2126, presented yesterday in the Plenary Session by Dr. Andrew Weng, highlighted how these astute investigators took a rare association and helped dissect out a new association of gain-of-function NOTCH1 mutations in T cell ALL. Translocations between chromosomes 7 and 9 are a rare event in human T cell ALL. NOTCH1 was originally discovered through its involvement in this translocation event. Dr. Weng and colleagues reported during their presentation that more than half of all human T cell ALL cell samples have activating NOTCH1 mutations. These mutations may occur as amino acid substitutions in an extracellular heterodimerization domain or as frameshift and stop codon mutations that result in the deletion of a C-terminal PEST destruction box. Thus, NOTCH1 mutations appear to be a common theme or underpinning genetic event in many forms of T cell ALL, each of which may have other mutations or translocations. Conversely, NOTCH1 mutations were not found in patient samples with B cell ALL, nor were they discovered in T cell ALL patient samples after attainment of remission. What’s even more amazing than these associations of NOTCH1 in human TALL pathogenesis, is that these investigators also described potential ways to induce growth arrest — in other words, targeted therapeutics. They showed that they could induce growth arrest in T-ALL cell lines via an inhibitor of gamma secretase or via retroviral transduction of dominant negative Mastermindlike- 1. All in all, this should serve as a great example to young investigators that distinct clues to pathogenesis exist in clinical associations and relatively common laboratory tests. It just takes a keen mind to take these clues and dissect them out to find what lies underneath them.