HOXA9/IRX1 expression pattern defines two subgroups of infant MLL-AF4-driven acute lymphoblastic leukemia
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Published on: March 31, 2019
Vasiliki Symeonidou1, Katrin Ottersbach1
1Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK.
Insights
Infant acute lymphoblastic leukemia (ALL) with t(4;11) is aggressive. Researchers identified two subgroups, iALL-HOXA9 and iALL-IRX1, based on gene expression, revealing distinct biological differences and potential therapeutic implications.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Infant acute lymphoblastic leukemia (ALL) with t(4;11) is a common and aggressive malignancy.
- Prognosis for infant ALL has remained poor, necessitating deeper understanding of its molecular underpinnings.
Purpose of the Study:
- To investigate the global transcriptomes of infant t(4;11) ALL subgroups.
- To identify molecular differences between subgroups defined by homeobox gene expression.
Main Methods:
- Analysis of two public RNA-sequencing datasets.
- Identification of mutually exclusive gene expression patterns (HOXA9/HOXA10 vs. IRX1).
Main Results:
- Two distinct subgroups, iALL-HOXA9 and iALL-IRX1, were identified based on HOXA9/HOXA10 and IRX1 expression.
- The iALL-IRX1 subgroup exhibited a more aggressive nature, younger age at diagnosis, and worse prognosis.
- Significant transcriptional differences were found between the subgroups, impacting potential treatment strategies.
Conclusions:
- Infant t(4;11) ALL comprises distinct molecular subgroups (iALL-HOXA9 and iALL-IRX1).
- The iALL-IRX1 subgroup's aggressive phenotype suggests an earlier cell of origin.
- Recognizing these subgroup differences is crucial for developing tailored treatment approaches.
Abstract:
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.
