Flash Talk + Poster Presentation 38th Lorne Cancer Conference 2026

Mechanistic insights into how venetoclax-based therapy durably eradicates NPM1 mutated clones in acute myeloid leukaemia (#101)

Chong Chyn Chua 1 2 3 , Natasha Anstee 1 4 , Giovanna Pomilio 1 , Rhiannon Morris 1 4 , Vajiranee Malalasekera 1 4 , Adam Ivey 5 , Noorul Amin 1 , Natasha Silke 1 , John Silke 1 4 , Nadia Davidson 1 4 , Andrew H Wei 1 4 6 , Fiona C Brown 1 4
  1. Walter and Eliza Hall Institute, Parkville, VICTORIA, Australia
  2. Department of Haematology, Monash Hospital and Monash University, Melbourne, VIC, Australia
  3. Northern Hospital, Epping, VIC, Australia
  4. Department of Medical Biology, The University of Melbourne, Melbourne, VIC, Australia
  5. The Alfred Hospital, Melbourne, VIC, Australia
  6. Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

Introduction

NPM1 mutation (mut) is the commonest genomic variant in acute myeloid leukemia (AML). Although combination regimens incorporating venetoclax (VEN) are highly effective at eliminating NPM1mut clones, the mechanism underlying this clinical sensitivity is unknown. To interrogate this, we performed orthogonal studies using AML patient samples and a model system of NPM1mut to reveal a role for suppressed NIBAN1 in mediating enhanced, but TP53 dependent sensitivity to VEN.

 

Methods

Targeted NGS and single cell (sc) multiomic assessments were performed on serial samples from patients with NPM1mut AML receiving VEN in combination with intensive chemotherapy (IC). Doxycycline inducible NPM1 wild type (wt) and mut overexpression models and target gene editing by CRISPR/Cas9 were generated in MOLM-13 cells.

 

Results

After VEN plus IC, overall survival for patients with NPM1mut (n=20) vs NPM1wt (n=65) AML was 43.9 vs 15.1 months, respectively (p=0.04). A 7-day monotherapy exposure to VEN led to a 66% relative reduction in bone marrow blasts in NPM1mut patients. VEN plus IC eliminated detectable (MRDneg) NPM1mut in 71% of patients. At relapse, only 3/8 patients had recurring NPM1mut clones. Serial sc-multiomic studies were performed on a patient who relapsed without detectable NPM1mut. Syngeneic MOLM-13 cell line models permitting inducible expression of either NPM1mut or wt control showed that NPM1mut but not NPM1wt enhanced VEN sensitivity. DEG analysis of NPM1mut vs wt from sc-RNAseq of patient AML blasts was integrated with bulk RNA seq of inducible NPM1 cell line models revealing NPM1mut associated reduction in expression of the cell stress response gene NIBAN1. Depletion of NIBAN1 phenocopied the enhanced sensitivity to VEN mediated by NPM1mut in a TP53 dependent manner.

 

Conclusion

VEN plus IC is the first therapy to reliably alter the natural history of human NPM1mut AML. The sensitivity to VEN is associated with reduced NIBAN1 expression. Future targeting of NIBAN1 may represent a novel approach to enhance VEN activity more broadly in TP53 wt AML.