HOXA9/IRX1 expression pattern defines two subgroups of infant MLL-AF4-driven acute lymphoblastic leukemia

• Published in: Experimental hematology 2021-01, Vol.93, p.38-43.e5
• Main Authors: Symeonidou, Vasiliki, Ottersbach, Katrin
• Format: Article
• Language: English
• Subjects: Adolescent; Brief Communication; Child; Gene Expression Regulation, Leukemic; Homeodomain Proteins - genetics; Humans; Infant; Myeloid-Lymphoid Leukemia Protein - genetics; Oncogene Proteins, Fusion - genetics; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Transcription Factors - genetics; Transcriptome
• ISSN: 0301-472X; 1873-2399
• DOI: 10.1016/j.exphem.2020.10.002

•We identified two sub-groups of infant MLL-AF4-driven ALL, iALL-HOXA9, and iALL-IRX1.•The subgroups exhibit mutually exclusive expression of HOXA9/HOXA10 and IRX1.•The transcriptional profile of iALL-IRX1 patients revealed a more aggressive disease.•The two subgroups exhibit different expression of potential therapeutic targets. Infant t(4;11) acute lymphoblastic leukemia is the most common leukemia in infant patients and has a highly aggressive nature. The patients have a dismal prognosis, which has not improved in more than a decade, suggesting that a better understanding of this disease is required. In the study described here, we analyzed two previously published RNA-sequencing data sets and gained further insights into the global transcriptomes of two known subgroups of this disease, which are characterized by the presence or absence of a homeobox gene expression signature. Specifically, we identified a remarkable mutually exclusive expression of the HOXA9/HOXA10 and IRX1 genes and termed the two subgroups iALL-HOXA9 and iALL-IRX1. This expression pattern is critical as it suggests that there is a fundamental difference between the two subgroups. Investigation of the transcriptomes of the two subgroups reveals a more aggressive nature for the iALL-IRX1 group, which is further supported by the fact that patients within this group have a worse prognosis and are also diagnosed at a younger age. This could be reflective of a developmentally earlier cell of origin for iALL-IRX1. Our analysis further uncovered critical differences between the two groups that may have an impact on treatment strategies. In summary, after a detailed investigation into the transcriptional profiles of iALL-HOXA9 and iALL-IRX1 patients, we highlight the importance of acknowledging that these two subgroups are different and that this is of clinical importance.