Slide 1: MLL-Menin inhibition reverses pre-leukemic progenitor self-renewal induced by NPM1 mutations
Abstract #546 MLL-Menin inhibition reverses pre-leukemic progenitor self-renewal induced by NPM1 mutations and prevents AML development Hannah Uckelmann
Slide 2: Progression from Stem or Progenitor to Leukemia Stem Cell
Progression from Stem or Progenitor to Leukemia Stem Cell NPM1c? MLL-AF9 MLL-AF9 DNMT3a HOX/Meis1 HOX/Meis1 DNMT3a NPM1c? DNMT3a DNMT3a DNMT3a DNMT3a NPM1c? NPM1c? DNMT3a DNMT3a Can progenitors act as the leukemia NPM1c initiating population in NPM1c AML?
Slide 3: MLL-r and NPM1c AML share common HOX signature and dependencies
MLL-r and NPM1c AML share common HOX signature and dependencies Menin-MLL inhibition HOX expression in AML MLL-r NPM1c+ HSCs HOXA HOXB Menin interaction domain Meis1 Modified from Spencer et al. Leukemia 2015 Can MLL-Menin inhibition reverse NPM1c induced self-renewal program? Michael W.M. Kühn et a
Slide 4: NPM1c maintains "stem cell program" in committed hematopoietic progenitors
NPM1c maintains “stem cell program” in committed hematopoietic progenitors. HSCs Sort GMPs MxCre NPM1cflox-cA/+ Gene expression RNAseq GMP LSK B WT NPM1c WT NPM1c C LT-HSC Signature: A HoxA9 FDR -- 0.19 NES – 1.32 P – 0.033 4 weeks post pIC
Slide 5: NPM1c induces "stem cell program" in hematopoietic progenitors
NPM1c induces “stem cell program” in hematopoietic progenitors. NPM1cflox-cA/+ DNMT3aR878H/+ Gene expression HoxA9 in vivo level in vivo level
Slide 6: NPM1c expression increases self-renewal of GMPs
NPM1c expression increases self-renewal of GMPs 4 wks Transplant GMPs MxCre NPM1cflox-cA/+ CFU DNMT3aR878H/+ A B Transplantation CFU Assay
Slide 7: Self-renewing NPM1c+ GMPs are leukemia initiating cells in NPM1c+ AML
Self-renewing NPM1c+ GMPs are leukemia initiating cells in NPM1c+ AML Survival Spleen Liver H&E A B C WT GMP-derived LSK-derived
Slide 8: Self-renewing NPM1c+ GMPs can be targeted by Menin-i
Self-renewing NPM1c+ GMPs can be targeted by Menin-i GMPs LT-GMPs Control 12 weeks Menin-i VTP-50469 GMP - NPM1c/DNMT3a Blood – Engraftment Survival A B NPM1c/DNMT3a LT-GMP B220 GFP CD45.2 CD11b weeks
Slide 9: Meis1 is repressed by VTP-50469 in NPM1c mutant cells
Meis1 is repressed by VTP-50469 in NPM1c mutant cells NPM1c regulated genes RNAseq A B Top Ten DOWN VTP: NES: -3.79 FDR: 0 p-value: 0 C ChIPseq D In vitro Rescue 10nM VTP-50469 Menin DMSO VTP DMSO MLL VTP Meis1
Slide 10: Human NPM1c AML are highly sensitive to VTP-50469 Menin-i treatment
Human NPM1c AML are highly sensitive to VTP-50469 Menin-i treatment hCD45 Engraftment %CD11b Survival – NPM1c+ PDX NPM1c; FLT3 ITD; PHF6 A B C n=5 n=9 D HOX cofactors: Control VTP-treated Pbx3 Meis1
Slide 11: MLL-Menin inhibition reverses progenitor self-renewal induced by NPM1c
MLL-Menin inhibition reverses progenitor self-renewal induced by NPM1c DNMT3a DNMT3a NPM1c DNMT3a DNMT3a DNMT3a DNMT3a NPM1c DNMT3a Menin-i DNMT3a NPM1c HOXA/B
Slide 12: Acknowledgements
Acknowledgements Scott Armstrong Matt Hemming Brandon Aubrey Taka Hoshii Haihua Chu Stephanie Kim Jevon Cutler Sayuri Kitajima Stephen Deangelo Andrei Krivtsov Zhaohui Feng Chloe Matovina Liz Frank Naomi Olsen Pablo Freire Sarah Perlee Jay Gadrey Florian Perner Hugh Giovinazzo Jen Perry Charlie Hatt