CUX1 mutation

In patients treated with intensive cytarabine-based inductions, the median overall survival was 26...Two patients with CUX1mut AML were treated with first-line venetoclax and a hypomethylating agent...These findings may explain a higher proportion of patients harboring CUX1 mutations that have ELN 2022 adverse-risk disease. While we did not detect any significant survival differences between patients with and without CUX1 mutations, larger cohorts are needed to confirm the prognostic impact of these rare mutations in AML.

Higher RBC-TI rates were observed in patients with various baseline mutational profiles treated with imetelstat compared with placebo in IMerge. While the sample size for specific mutations was small, consistent with the observation that patients with LR-MDS have a low number of specific mutations, TI responses in patients receiving imetelstat occurred regardless of the presence of mutations associated with poor prognosis or the number of mutations. Imetelstat showed comparable TI rates across different molecularly defined subgroups, suggesting that clinical benefit of imetelstat in patients with LR-MDS is independent of the underlying molecular pattern.

DDX41 mut MNs have distinct genetic and clinical/hematological features, representing a unique subset of MNs. IPSS-R/IPSS-M prognostication may not be applied to DDX41 mut MDS.

Similarly, low expression of CUX1 in primary AML samples correlates with sensitivity to the same inhibitors, suggesting a potential therapy for malignancies with CUX1 inactivation. This work demonstrates an unexpected convergence of an oncogene and tumor suppressor gene on the same pathway.

Initial real-world data of the ongoing study demonstrate the power of WGTS to add valuable information to gold standard diagnostics in 1/3 of unclear cases within 3 weeks. In the context of challenging unsolved cases, close cooperation of experts from various backgrounds (hematology, pathology, human genetics and bioinformatics) in tumor boards allows to achieve the best possible diagnoses for patients.

DDX41mut MNs have distinct genetic and clinical/hematological features, representing a unique subset of MNs. IPSS-R/IPSS-M prognostication may not be applied to DDX41mut MDS.

Existing inhibitors are available for CUL1 (MLN4924), CUX1 (BER modulating agents) and EZH2 (EPZ6438, GSK343), but the presence of homozygous mutations (UPD7q) argues that EZH2 inhibition is unlikely to be successful. In conclusion, we showed a comprehensive molecular topography of -7/del7q and identified novel HI genes which could be targeted by novel or repurposed drugs. Ongoing drug screens for identified targets performed in cells with -7/del7q will be presented at the meeting.

CUX1 mutations are seen with adverse prognostic features and could be a late clonal evolutional event of myeloid disorders. The differences between CUX1 tier I/tier II and VUS underscore the importance of accurate variant classification in reporting of multigene panels.