Background: The CUX1 gene, known as CUT-like homeobox 1, is located on chromosome 7q22.1 and encodes several protein isoforms, particularly CUX1p200, a transcription factor which acts as a tumor suppressor. CUX1 mutations are recurrently observed in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). The purpose of this study is to evaluate the characteristics and clinical significance of CUX1 mutations in patients with AML.

Methods: This single-center retrospective study identified 22 patients with newly diagnosed, treatment naïve AML with a somatic CUX1 mutation between 2018 and 2025. Mutations were detected in our next-generation sequencing assay with a limit of detection greater than 2% variant allele frequency (VAF). We evaluated associations with molecular features, including co-occurring somatic mutations, prognostic factors, and outcomes.

Results: The race/ethnicity of patients included non-Hispanic whites (n=15), non-Hispanic blacks (n=3), Hispanics (n=3), and Asians (n=1). Fifty-nine percent of patients were male and 41% female. Eight patients (36%) had prior myeloid neoplasms with transformation into AML, including MDS (n=5), myeloproliferative neoplasm (n=2), and chronic myelomonocytic leukemia (n=1). Two patients (9%) had a prior history of allogeneic stem cell transplant (SCT) for myeloid neoplasms before the progression to AML. The median age was 71 years (range 57-83). The median white blood cell count, hemoglobin, and platelet count were 6.3 K/uL, 8.4 g/dL, and 58 K/uL, respectively.

CUX1 mutations were detected in 14 patients at the time of or before the diagnosis of AML, while the remaining eight patients had CUX1 mutations in subsequent tests after initial diagnosis. By the European Leukemia Network (ELN) 2022 risk stratification, 20 (91%) of the patients had adverse cytogenetic risk. The CUX1 mutation coincided with other somatic mutations, the most common being ASXL1 (45%), TET2 (41%), and SRSF2 (41%). Other frequently co-mutations included RUNX1 (23%), TP53 (23%), DDX41 (18%), NRAS (18%), CBL (18%), JAK2 (18%), DNMT3A (18%), STAG2 (14%), PTPN11 (14%), and U2AF1 (14%).

Induction therapy included a low-intensity therapy of a hypomethylating agent and venetoclax (91%), while 9% of patients received high-intensity chemotherapy. Among the 22 patients, 20 were evaluable for response of measurable residual disease (MRD) by flow cytometry after induction therapy and 16 (80%) of them had detectable MRD. Four (20%) patients achieved complete remission after induction therapy. Three patients (14%) underwent allogeneic SCT. Given the limited number of patients, no prognostic factors were identified, except hemoglobin at the time of diagnosis of AML (HR, 0.486; 95% CI, 0.285-0.829; P=0.008). Among 22 patients with newly diagnosed CUX1-mutated AML, the median event-free survival (EFS) and overall survival (OS) were 1.4 and 6.2 months, respectively. With median follow-up of 50 months, the 4-year EFS and OS rates were 11% and 23%, respectively.

Conclusion:CUX1 mutations in AML are associated with prior antecedent myeloid neoplasms, poor response rates, high relapse risk, and poor overall outcomes. Given the poor outcomes, patients in complete remission after the first cycle of treatment should be considered for allogeneic SCT.

This content is only available as a PDF.
2025
Sign in via your Institution