Faculty, Staff and Student Publications
Publication Date
12-1-2024
Journal
Nature
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.
Keywords
Animals, Female, Humans, Mice, Antineoplastic Agents, Bridged Bicyclo Compounds, Heterocyclic, Cell Lineage, Drug Resistance, Neoplasm, Leukemia, Myeloid, Acute, Monocytes, Mutation, Neoplastic Stem Cells, Proto-Oncogene Proteins c-bcl-2, ras Proteins, Sulfonamides, Granulocytes, Clone Cells, Stem Cells, Recurrence
DOI
10.1038/s41586-024-08137-x
PMID
39478230
PMCID
PMC11618090
PubMedCentral® Posted Date
10-30-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Medical Genetics Commons, Oncology Commons