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July 17th, 2025
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All India Institute of Medical Sciences, New Delhi, India
cancer biology
biorxiv

The HOTAIRM1-miR-222 Axis Regulates Venetoclax Resistance and Defines a High-Risk Subset in Pediatric t(8;21) Acute Myeloid Leukemia

Wilson, C.Open in Google Scholar•Swaroop, P.Open in Google Scholar•Gaur, V.Open in Google Scholar•Sharma, D.Open in Google Scholar•Bhardwaj, T.Open in Google Scholar•Kumar, S.Open in Google Scholar•Chopra, A.Open in Google Scholar•Ghose, S.Open in Google Scholar•Palanichamy, J. K.Open in Google Scholar•Pushpam, D.Open in Google Scholaret al.

Although acute myeloid leukemia (AML) with the RUNX1::RUNX1T1 fusion [t(8;21)(q22;q22.1)] defines a distinct cytogenetic subtype, differences in treatment response suggest additional molecular contributors beyond chromosomal abnormalities. Long non-coding RNAs (lncRNAs) regulate haematopoiesis and leukemogenesis. To investigate their role in t(8;21) AML, we performed whole-transcriptome sequencing of pediatric patients and age-matched healthy controls, identifying significant downregulation of lncRNA HOTAIRM1, a regulator of myeloid differentiation (adjusted P < 0.05). This was confirmed in three datasets: single-cell RNA-sequencing (GSE116256), the Leukemia MILE study (GSE13159, P=0.03), and the current study (P<0.0001). Analysis of downstream pathways activated by HOTAIRM1 loss identified miR-222, an oncomiR, as a de-repressed target (P=0.01). Elevated miR-222 expression was observed across AML cell lines (P<0.05), leukemic stem and progenitor cells (GSE117090, P<0.05), AML plasma-derived exosomes (GSE142699, P<0.0001), the current study dataset (P<0.0001), and the TARGET AML dataset (P<0.0001). Restoring HOTAIRM1 expression with epigenetic agents azacytidine and panobinostat induced apoptosis in venetoclax-resistant Kasumi-1 cells (P<0.01), through suppression of miR-222 (P<0.01) and downregulation of anti-apoptotic proteins BCL-xL and MCL-1 (P<0.05), key mediators of the venetoclax resistance mechanism. Machine learning based feature selection and Cox regression analysis showed that high miR-222 expression predicts poor outcome in pediatric t(8;21) AML, validated in both our institutional pediatric AML cohort (P<0.05) and the multi-institutional TARGET cohort (P<0.0001). Together, our findings highlight an epigenetic based approach to restore HOTAIRM1 pathway function in venetoclax-resistant AML cells, and identify miR-222 as a prognostic marker to refine risk stratification within the traditionally favorable-risk t(8;21) AML subgroup.

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