# Prognostic significance of CUX1 genomic deletion in myelodysplastic neoplasms

## TL;DR

This study finds that CUX1 genomic deletion in myelodysplastic neoplasms is strongly linked to chromosome 7 abnormalities and high-risk features but does not independently predict survival beyond existing molecular scores.

## Contribution

The study clarifies that CUX1 deletion reflects chromosome 7 biology and does not add independent prognostic value beyond current molecular scoring systems in MDS.

## Key findings

- CUX1 loss occurs in 26% of MDS patients and is nearly always associated with chromosome 7 abnormalities.
- CUX1 loss correlates with higher blast counts, worse IPSS-R and IPSS-M scores, and co-occurrence with EZH2 alterations.
- After adjusting for IPSS-M, CUX1 loss does not independently predict survival outcomes.

## Abstract

Molecular profiling has transformed risk stratification in myelodysplastic neoplasms (MDS). However, the independent prognostic value of specific genomic alterations beyond comprehensive molecular scoring remains unclear. We investigated whether CUX1 copy-number loss (haploinsufficiency) adds prognostic value and its association with other mutations. Given its correlation with chromosome 7 abnormality, we examined its independent significance within the current MDS molecular framework.

A cohort of 501 MDS patients with available CUX1 copy-number data (CNACS gene-level calls) and complete clinical follow-up was analyzed from cBioPortal. We assessed associations with clinical characteristics, co-occurring alterations, and survival. Cox proportional hazards models evaluated independence adjusting for IPSS-R and IPSS-M.

CUX1 loss occurred in 129/501 patients (26%), nearly always with − 7/del(7q) (98%). Patients with CUX1 loss had higher marrow blasts (median 7% vs. 4%, P < 0.001), IPSS-R scores (6.9 vs. 4.6), and IPSS-M scores (2.33 vs. 0.79). CUX1 loss strongly associated with EZH2 alterations (OR 223.8) and complex karyotype (60%). In univariable analysis, CUX1 loss predicted inferior overall survival (OS; median 11.8 vs. 27.1 months; HR 2.39, 95%CI 1.85–3.08, P < 0.001) and leukemia-free survival (LFS; HR 2.30, 95%CI 1.78–2.98, P < 0.001). After IPSS-M adjustment, associations were non-significant (OS HR 1.27, P = 0.11; LFS HR 1.23, P = 0.15) with negligible incremental discrimination. Within the − 7/del(7q) subgroup, no survival difference was detected (OS P = 0.41; LFS P = 0.31).

CUX1 loss identifies high-risk MDS with − 7/del(7q) and EZH2 co-alterations but provides no independent prognostic information beyond IPSS-M. Isolated CUX1 deletions are rare. CUX1 loss reflects − 7/del(7q) biology rather than independent prognostic significance.

The online version contains supplementary material available at 10.1007/s00277-026-06936-y.