Abstract / Summary
Deletion of the long arm of chromosome 5 is a defining cytogenetic abnormality in the myelodysplastic neoplasm with low blasts and isolated del(5q)(MDS-5q); however, it is also frequently observed in other myeloid neoplasms (MN), including MN post-cytotoxic therapy with del(5q) [(MN-pCT)-del(5q)]. Although isolated del(5q) has traditionally been considered indicative of de novo disease, emerging evidence demonstrates that similar cytogenetic findings may arise in biologically distinct contexts with markedly different clinical implications. In this review, we focus on the comparison between MDS-5q and MN-pCT-del(5q). Mechanistically, MDS-5q is primarily driven by the haploinsufficiency of genes within commonly deleted regions on chromosome 5q, including RPS14 and regulatory microRNAs, resulting in lineage-restricted dysplasia and a relatively favorable prognosis, whereas del(5q) in MN-pCT-del(5q) typically arises from genotoxic stress and genomic instability and is often associated with complex karyotypes and adverse molecular features such as TP53 mutations. Structural differences, including interstitial versus terminal deletions, may further reflect distinct underlying mechanisms of genomic rearrangement. A key advance is the recognition that del(5q) frequently occurs within a broader framework of clonal hematopoiesis of indeterminate potential (CHIP). CHIP-associated mutations in genes such as DNMT3A, TET2, and ASXL1 are commonly identified and potentially precede or coexist with del(5q), thereby contributing to clonal fitness and disease evolution. Both “CHIP-first” and “del(5q)-first” evolutionary trajectories likely contribute to disease pathogenesis, underscoring the importance of clonal context in determining clinical behavior. In this framework, del(5q) is best characterized as a context-dependent event within dynamic clonal architecture, with important implications for risk stratification and therapeutic decision-making.