Nidogen-1, a Novel Player in KMT2A-Rearranged Pediatric Acute Myeloid Leukemia Patients, Expressed in the Leukemic Stem Cell

The outcome for children with acute myeloid leukemia (AML) has improved significantly over the past decades, however overall survival rates now reach a plateau of 75%. Furthermore, 30-40% of the patients still relapse, and less than half will be cured long-term, but with an increased burden of side effects due to high cumulative doses of chemotherapy and for some patients a hematopoietic stem cell transplantation. The high relapse rates have been shown to be caused by the leukemic stem cell (LSC). Therefore, there is an unmet medical need to better characterize and target this aggressive cell population to improve the event-free and overall survival for these patients.

We recently explored mRNA (n = 27071 transcripts) expression in pediatric AML (pedAML) subpopulations (LSC and leukemic blasts) and their healthy counterparts (hematopoietic stem cells (HSC) and control myeloblast, respectively). Nidogen-1 (NID1) was found to be overexpressed in both LSC and leukemic blasts subpopulations, and was absent in the HSC. These observations were validated in public datasets and in different hematological cell lines (n = 11) using RT-qPCR, illustrating that the expression was highly specific for AML. Kaplan Meier survival curves and univariate cox analysis revealed that high NID1 expression is significantly associated with worse overall and event-free survival of pedAML patients (n=1029, TARGET AML program). Additional examination of the clinical and molecular characteristics of these patients revealed that NID1 expression is significantly associated with KMT2A rearrangements, further confirmed by RT-qPCR in AML cell lines (n=8) and in an independent pedAML cohort (n=160, St. Jude expression database).

We generated NID1 knockdown and overexpression cell lines and performed drug response profiling. This revealed a differential sensitivity of both models for HSP90 inhibition. Morover, RNA sequencing and gene set enrichment analysis between NID1^high and NID1^low phenotypes of the NID1 knockdown and overexpression cell line and KMT2A::MLLT3 rearranged pedAML patients showed involvement of NID1 in metabolic pathways known to be enriched in the LSC.

Altogether, this study highlights NID1 as a novel potential oncogene associated with worse overall and event-free survival and a metabolic LSC phenotype in AML. Research should focus on the molecular and functional characterization of the LSCs capacity to circumvent treatment and re-initiate leukemia, since the identification of unique surface antigens on the LSCs has proven to be difficult due to the high resemblance with the HSC. Therefore, the association with KMT2A rearrangements and the absent expression in the HSC emphasizes that NID1 could serve as an interesting biomarker and help us to further map this aggressive cell population and establish potential therapeutic strategies tackling the high relapse rates in pedAML patients.

No relevant conflicts of interest to declare.