Acute myeloid leukemia (AML) stems from impaired differentiation of myeloid progenitor cells in the bone marrow. This results in the accumulation of immature precursor cells within the bone marrow and circulation, ultimately impairing hematopoiesis, or blood cell production, and other essential biological functions. One subtype of AML—acute promyelocytic leukemia (APL)—can be treated with a pair of drugs (all-trans retinoic acid and arsenic trioxide) that push cancerous precursors past the differentiation barrier. But there remains a pressing need to identify similar strategies for other AML subtypes. Inhibiting the epigenetic enzyme LSD1, which is highly expressed in AML cells, induces differentiation in AML stem cells. But LSD1 inhibitors have proved too toxic at the doses required to be viable for use as a monotherapy. Researchers co-led by Ludwig Oxford’s Yang Shi and Amir Hosseini published a pair of papers this spring that addressed this issue in distinct ways.
In the first, led by Amir and Yang—along with colleagues in Finland and the U.S.—they reported in an April publication in Nature that an inhibitor of the GSK3α/β enzyme, a driver of the WNT signaling pathway, synergizes with low doses of an LSD1 inhibitor to drive AML precursor cell differentiation, inhibit cancer cell proliferation and extend the survival of mice engrafted with human AML cells. The combination rewires gene expression programs to suppress the stem cell-like traits of leukemic cells. It also induces a gene expression signature in leukemic cells similar to that seen in AML patients who live relatively longer with the cancer. The researchers showed that the combo selectively targets leukemic cells—not healthy hematopoietic ones—lowering the risk of toxicity in patients.
The second study took an entirely different tack to disrupt LSD1 activity in AML. LSD1’s epigenetic function—reversing histone methylation at lysine residues—is only one aspect of its part in AML oncogenesis. The enzyme also serves as a scaffolding protein that stabilizes protein complexes on chromatin that are central to AML pathology. Researchers led by Amir, Yang and Jian Jin at the Icahn School of Medicine at Mount Sinai in New York, described a proteolysis-targeting chimera (PROTAC) degrader, MS9117, that binds LSD1 and targets it for ubiquitination—a chemical tag that ultimately marks it for destruction by the cell’s protein-degrading machinery. They showed that MS9117, the first LSD1 inhibitor of this kind, effectively degrades LSD1 and suppresses the proliferation of AML cells in culture more effectively than pharmacological inhibitors of the enzyme. They also demonstrated that it sensitizes non-APL cells to treatment with all-trans retinoic acid.
Perturbing LSD1 and WNT rewires transcription to synergistically induce AML differentiation
Nature, 2025 April 16
Discovery of an LSD1 PROTAC degrader
PNAS, 2025 May 14