RAS-mutant leukaemia stem cells drive clinical resistance to venetoclax

Area of Science:

• Hematology
• Cancer Biology
• Molecular Oncology

Background:

• RAS mutations are consistently observed late in acute myeloid leukemia (AML) progression or relapse.
• The biological reasons for the late acquisition of RAS mutations in AML remain unclear.

Purpose of the Study:

• To investigate the mechanistic basis for the obligatory late acquisition of RAS mutations in AML.
• To elucidate how RAS mutations influence leukemia stem cell (LSC) hierarchy and therapeutic response.

Main Methods:

• Utilized human leukaemogenesis models to study the temporal order of mutation acquisition.
• Analyzed the transformation potential of mutant RAS in specific hematopoietic progenitor cells.
• Examined BCL2 family gene expression and venetoclax sensitivity in RAS-mutant versus RAS-wild-type LSCs.

Main Results:

• RAS mutations are obligatory late events in AML, dependent on cooperating mutations.
• Mutant RAS specifically transforms granulocyte-monocyte progenitors with pre-existing drivers, altering the LSC origin.
• RAS-mutant LSCs exhibit altered BCL2 family gene expression, conferring resistance to venetoclax and leading to monocytic AML with poor treatment outcomes.

Conclusions:

• RAS mutations shape AML's non-genetic cellular hierarchy by restricting LSC target cells.
• RAS-driven alterations in LSCs contribute to venetoclax resistance and monocytic relapse in AML patients.