Chronic lymphocytic leukemia (CLL) is the most frequent adult leukemia in the west. The clinical course and eventual outcome of CLL is remarkably heterogeneous.
As a consortium, we have sequenced >1000 CLL samples with more than 28 genes or genomic regions. We showed the importance of quantifying the percentage of cells carrying each specific mutation and reconstructed their evolutionary trajectories.
This shows 1) copy number alterations (CNA) tend to be acquired early whereas gene mutations usually occur later during CLL progression. 2) Total number of driver alterations is associated with shortened the time to first treatment. 3) Increasing subclonal heterogeneity (accumulation of driver alterations in subclones) was best at predicting overall survival of the patients. 4) The mutation profiles are very similar between monoclonal
B-cell lymphocytosis and ultra-stable chronic lymphocytic leukemia 5) No topographic differences were observed for mutations in known driver genes such as NOTCH1 , TP53 , ATM , SF3B1 , IRF4 and DDX3X . 5) We reported a novel U1 mutation which identifies a subgroup of patients with aggressive disease 6) Complex karyotype CLL represents a heterogeneous group with variable clinical behavior.
We also investigated the functional relationship between mutation, drugs and microenvironment. We developed a novel software, called multi-omics factor analysis (MOFA), which identify common underlying factors (latent variables) shared between the drug response data and the ‘omics datatypes. In vitro analyses of drug response showed that somatic mutations influence drug responses in CLL.
We showed that the heterogeneity in energy metabolism may be therapeutically exploited in the selection of therapeutic strategies. Experimentally, microenvironmental stimuli affect EZH2 expression and function in CLL and combined B-cell signaling and EZH2 inhibition showed synergistic effects on primary CLL cells. We also uncovered that in vivo ibrutinib treatment reprograms CLL cell signaling capacity in a heterogeneous manner.