shRNA screening identifies JMJD1C as being required for leukemia maintenance

Area of Science:

• Epigenetics
• Cancer Biology
• Hematology

Background:

• Epigenetic regulators are key in acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL) pathogenesis.
• Cancer cells may depend on epigenetic regulators for survival and proliferation, presenting potential therapeutic targets.
• Drug intervention targeting epigenetic control proteins shows promise, but specific dependencies remain largely unknown.

Purpose of the Study:

• To identify novel drug targets for leukemia by screening for epigenetic regulators essential for cancer cell survival.
• To investigate the role of epigenetic regulators in the context of MLL-AF9-driven AML and MLL-rearranged ALL.

Main Methods:

• Utilized a mouse model of MLL-AF9-induced AML.
• Employed an epigenetic short hairpin RNA (shRNA) library for target screening.
• Conducted counter-screens using normal mouse bone marrow cells to assess general shRNA toxicity.
• Validated candidate targets in mouse and human leukemic cell lines, including SEM (MLL-rearranged ALL).

Main Results:

• Identified Jmjd1c as a significant candidate drug target.
• Depletion of Jmjd1c inhibited growth and colony formation in mouse MLL-AF9 AML cells.
• Jmjd1c depletion impaired expansion and colony formation in human leukemic cell lines, notably MLL-rearranged ALL.
• Growth defects upon Jmjd1c depletion were linked to increased apoptosis in both mouse and human leukemic cells.

Conclusions:

• Jmjd1c is essential for the survival and proliferation of leukemic cells.
• Jmjd1c represents a potential therapeutic target for treating AML and ALL.
• Further investigation into Jmjd1c as a drug target is warranted for leukemia treatment.