RAS-mutant leukaemia stem cells drive clinical resistance to venetoclax

Junya Sango, Saul Carcamo, Maria Sirenko, Abhishek Maiti, Hager Mansour, Gulay Ulukaya, Lewis E. Tomalin, Nataly Cruz-Rodriguez, Tiansu Wang, Malgorzata Olszewska, Emmanuel Olivier, Manon Jaud, Bettina Nadorp, Benjamin Kroger, Feng Hu, Lewis Silverman, Stephen S. Chung, Elvin Wagenblast, Ronan Chaligne, Ann-Kathrin Eisfeld, Deniz Demircioglu, Dan A. Landau, Piro Lito, Elli Papaemmanuil, Courtney D. DiNardo, Dan Hasson, Marina Konopleva and Eirini P. Papapetrou ()
Additional contact information
Junya Sango: Icahn School of Medicine at Mount Sinai
Saul Carcamo: Icahn School of Medicine at Mount Sinai
Maria Sirenko: Memorial Sloan Kettering Cancer Center
Abhishek Maiti: The University of Texas MD Anderson Cancer Center
Hager Mansour: Icahn School of Medicine at Mount Sinai
Gulay Ulukaya: Icahn School of Medicine at Mount Sinai
Lewis E. Tomalin: Icahn School of Medicine at Mount Sinai
Nataly Cruz-Rodriguez: Icahn School of Medicine at Mount Sinai
Tiansu Wang: Icahn School of Medicine at Mount Sinai
Malgorzata Olszewska: Icahn School of Medicine at Mount Sinai
Emmanuel Olivier: Icahn School of Medicine at Mount Sinai
Manon Jaud: Icahn School of Medicine at Mount Sinai
Bettina Nadorp: Division of Precision Medicine, NYU Grossman School of Medicine
Benjamin Kroger: University of Texas Southwestern Medical Center
Feng Hu: Memorial Sloan Kettering Cancer Center
Lewis Silverman: Icahn School of Medicine at Mount Sinai
Stephen S. Chung: University of Texas Southwestern Medical Center
Elvin Wagenblast: Icahn School of Medicine at Mount Sinai
Ronan Chaligne: Weill Cornell Medicine
Ann-Kathrin Eisfeld: The Ohio State University Comprehensive Cancer Center
Deniz Demircioglu: Icahn School of Medicine at Mount Sinai
Dan A. Landau: Weill Cornell Medicine
Piro Lito: Memorial Sloan Kettering Cancer Center
Elli Papaemmanuil: Memorial Sloan Kettering Cancer Center
Courtney D. DiNardo: The University of Texas MD Anderson Cancer Center
Dan Hasson: Icahn School of Medicine at Mount Sinai
Marina Konopleva: Albert Einstein College of Medicine
Eirini P. Papapetrou: Icahn School of Medicine at Mount Sinai

Nature, 2024, vol. 636, issue 8041, 241-250

Abstract: Abstract Cancer driver mutations often show distinct temporal acquisition patterns, but the biological basis for this, if any, remains unknown. RAS mutations occur invariably late in the course of acute myeloid leukaemia, upon progression or relapsed/refractory disease1–6. Here, by using human leukaemogenesis models, we first show that RAS mutations are obligatory late events that need to succeed earlier cooperating mutations. We provide the mechanistic explanation for this in a requirement for mutant RAS to specifically transform committed progenitors of the myelomonocytic lineage (granulocyte–monocyte progenitors) harbouring previously acquired driver mutations, showing that advanced leukaemic clones can originate from a different cell type in the haematopoietic hierarchy than ancestral clones. Furthermore, we demonstrate that RAS-mutant leukaemia stem cells (LSCs) give rise to monocytic disease, as observed frequently in patients with poor responses to treatment with the BCL2 inhibitor venetoclax. We show that this is because RAS-mutant LSCs, in contrast to RAS-wild-type LSCs, have altered BCL2 family gene expression and are resistant to venetoclax, driving clinical resistance and relapse with monocytic features. Our findings demonstrate that a specific genetic driver shapes the non-genetic cellular hierarchy of acute myeloid leukaemia by imposing a specific LSC target cell restriction and critically affects therapeutic outcomes in patients.

Date: 2024
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DOI: 10.1038/s41586-024-08137-x

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