HOXA10-AS in the pathogenesis of MLL-rearranged leukemias

Our latest article on long noncoding RNAs has been published in Blood Advances: “The stem cell-specific lncRNA HOXA10-AS in the pathogenesis of KMT2A-rearranged leukemia“. It features the work of a former medical student (now a resident of pediatrics) Sina Al-Kershi, whom we congratulate for her extraordinary hard work and persistence!

The importance of HOX genes in hematopoiesis is well-documented, as is their deregulation in leukemia cells. However, despite decades of intensive research on the coding HOX genes, the numerous long noncoding RNAs (lncRNAs) within the HOX clusters remain a mystery. We found one such lnRNA, HOXA10-AS, to be highly expressed in hematopoietic stem cells and NPM1-mutated and KMT2A (a.k.a. MLL)-rearranged leukemias. We proceeded to characterize its role in normal and malignant hematopoiesis.

In short, HOXA10-AS was shown to be required for the maintenance of MLL-rearranged acute myeloid leukemia (AML) cell lines through various loss-of-function approaches, while lentiviral expression in CD34+ hematopoietic stem and progenitor cells led to a differentiation block. High expression of HOXA10-AS associated with poor prognosis in adult and pediatric AML patient cohorts, and its depletion inhibited the proliferation of patient-derived xenografts in vivo. Mechanistically, HOXA10-AS localizes appears to act in trans to induce the NF-kB pathway. These findings place HOXA10-AS in the growing list of functionally validated lncRNAs with roles in normal and malignant hematopoiesis, and provides further evidence of the significance of lncRNAs in pathophysiological processes.

Back to blog overview

Other Blogposts