There has been great excitement in the CLL world about the paper in Nature which describes the first whole genome sequencing of four patients with CLL. The paper which has 65 authors comes from Spain, and hematologists will recognize the names of Emili Montserrat, Jesus San Miguel and Elias Campo among others.
Two of the patients had mutated and two unmutated IGHV genes. The whole genome sequencing identified 46 somatic mutations that might affect gene function. Further analysis of 363 patients identified four of these genes that were recurrently mutated, NOTCH1, Exportin 1 (XPO1), myeloid differentiation primary response gene 88 (MYD88) and kelch-like 6 (KLHL6). The first three of these were identified as oncogenic changes that contribute to the clinical evolution of the disease.
NOTCH1 was found to be mutated in 12% of CLLs. NOTCH1 is constitutively expressed in CLL but the mutations identified generate a more stable and active form of the protein. It was later found that 23 of the 46 original mutated genes were assigned to the NOTCH1 signaling pathway. Furthermore NOTCH1 mutated patients had a more advanced clinical stage, more adverse biological features, a more likely Richter's transformation (7/31 v 3/224), and a significantly shorter overall survival than those with an unmutated NOTCH1. The same IGHV clonal arrangement and the same NOTCH1 mutations were found in the diffise large B cells transformations studied as in the original corresponding CLLs.
A recurrent mutation of the MYD88 gene was found in 2.9% of CLLs and the same mutation has been detected in other lymphomas. This protein participates in the signaling pathways of IL-1 and Toll-like receptors during the immune response. This mutation was associated with increased cytokine secretion. Cytokine secretion has been associated with recruitment of Macrophages and T lymphocytes which create a favorable niche for CLL cell survival. Patients with this mutation tended to present at an earlier age and with a more advanced stage, but they tend to have mutated IGHV genes and not to have worse progression or survival rates.
A recurrent mutation at XPO1 occurred in four patients. XPO1 is implicated in the nuclear export of proteins including members of the MAP kinase pathway. Two of the four cases also had NOTCH1 mutations.
It was thought that the mutations of KLH6 were likely to be caused by the same follicular center mutating mechanism that is active for IGHV genes and which is known to spill over onto other genes including BLC6, MYC and PIM1.
NOTCH1 has been written about before on this blog and so have Toll-like receptors. It looks as though we have some new targets for therapy.