Characterisation of cells markers associated with IKZF1^plus in BCP-ALL

The presence of IKZF1 deletions has been associated with an increased relapse rate in B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). There is a particular subset of IKZF1^del cases called IKZF1^plus (defined by the co-occurrence of IKZF1^del and deletions in CDKN2A/B, PAX5, or the PAR1 region, in the absence of ERG deletions), which is also associated with worse prognosis, but some recent studies have not found major differences between the IKZF1^del and IKZF1^plus groups. Therefore, the IKZF1^plus group still needs further comprehension and our study aims to characterise the molecular heterogeneity and identify molecular markers exclusively associated with IKZF1^plus. Two independent series of cases (TARGET, n = 125 and GenLAb, n = 60) were evaluated by segregating patients into 3 groups: IKZF1^plus, IKZF1^del, and IKZF1^wild. Differential expression analyses showed that the membrane protein-coding genes most associated with the IKZF1^plus group were: KCNA5, GREB1, EPOR, SDK1, and PTPRB. Notably, KCNA5 and GREB1 differential expression levels were validated in the GenLAb validation series. Regarding copy number alterations, we observed a high frequency of VPREB1 deletions in the IKZF1^plus group, as well as additional exclusive deletions in the CD200 and BTLA genes. Recent research suggests that the importance of the IKZF1^plus profile varies depending on the genetic subgroup. In this scenario, we found associations between IKZF1^plus and certain genes in BCP-ALL, being KCNA5 and GREB1 the most promising biomarkers for predicting IKZF1^plus. A deeper understanding of these genetic profiles will allow a better risk assessment and offer precise rationale for therapeutic strategies in BCP-ALL.