Serine auxotrophy is a targetable vulnerability driven by PSAT1 suppression in AML.

Area of Science:

• Oncology
• Cancer Metabolism
• Biochemistry

Background:

• Serine metabolism and the serine synthesis pathway (SSP) are critical for cancer cell growth.
• Dietary restriction of serine and glycine (SG) shows potential in suppressing certain cancers, but sensitivity factors remain unclear, especially in acute myeloid leukemia (AML).

Purpose of the Study:

• To investigate the role of serine metabolism in AML.
• To identify determinants of sensitivity to dietary serine and glycine restriction in AML.
• To define a distinct metabolic subtype of AML.

Main Methods:

• Analysis of human AML cell lines and primary samples.
• Assessment of serine auxotrophy and its association with SSP enzyme expression (PSAT1, PHGDH).
• Evaluation of response to SG restriction in vivo and in combination with venetoclax.
• Correlation of MECOM rearrangement with PSAT1 suppression.

Main Results:

• A subset of AML exhibited serine auxotrophy, characterized by suppressed PSAT1 and inability to synthesize serine.
• These serine auxotrophic AMLs responded to SG restriction in vivo and were rescued by PSAT1 restoration.
• AML with SF3B1 K700E mutation showed additional dependence on PHGDH.
• SG restriction synergized with venetoclax in serine auxotrophic AML.
• MECOM rearrangement was strongly associated with PSAT1 suppression and serine auxotrophy.

Conclusions:

• A distinct metabolic subtype of AML dependent on external serine has been identified.
• This subtype is characterized by PSAT1 suppression and sensitivity to SG restriction.
• Targeting serine metabolism, particularly through SG restriction, represents a promising therapeutic strategy for this AML subtype.