Dong-Er Zhang
University of California-San Diego, CA·Biochemistry
Blood cancers arise when mutations in bone marrow stem cells push them to make the wrong cells in the wrong numbers. Two threads run through this lab's work.
- Fields
Biochemistry
Microbiology & Immunology
Medicine & Clinical Research
- Topics
type I interferon
JAK-STAT signaling
interferon stimulated genes
- Grants
- 3 known grants, through Jun 2031
What they work on
- Determine the clinical and molecular consequences of strengthening type I interferon signaling in cancer cells by targeting USP18, the enzyme the lab identified as the main brake on this pathway, in myeloproliferative neoplasm models.
- Identify and mechanistically characterize the E3 ligases that drive USP18 degradation in myeloproliferative neoplasms, as a foundation for molecular-glue compounds that force USP18 destruction.
- Evaluate the biological and therapeutic effects of modulating USP18 in an intact blood and immune environment using genetically engineered mouse models of myeloproliferative neoplasms and immunodeficient mice engrafted with human cells.
- Run a large phenotypic high-throughput screen for small molecules that break the USP18-mediated interferon feedback loop, using a biosensor cell line carrying CRISPR/Cas9-inserted fluorescent reporters of interferon signaling.
- Validate screening hits in secondary and mechanistic assays, mapping each compound to the specific component of the interferon feedback pathway it acts on, and test the anti-cancer potential of the resulting chemical probes.
- Analyze how the t(8;21) translocation, which produces the AML1-ETO fusion transcription factor, combines with KIT mutations to drive leukemia, using integrated transcriptome and epigenome studies in mouse models.
- Characterize the roles of the antioxidant glutathione and of oxidative phosphorylation in sensitizing t(8;21) acute myeloid leukemia cells to cell death.
More about the research
One concerns type I interferons, immune signaling proteins that slow tumor growth and that are needed for chemotherapy, radiation, and immunotherapy to work well. Their usefulness as drugs is limited because cells quickly shut the signal down through a built-in brake. The lab cloned the mouse and human genes for USP18, an enzyme it identified as the main brake on interferon signaling, and is now pursuing both the biology of releasing that brake and small molecules that could do it. The other thread concerns acute myeloid leukemia carrying a specific chromosome rearrangement, and what makes those leukemia cells vulnerable.
Why it matters
Interferon treatment has been tried in more than ten cancer types with disappointing results, largely because cells shut the signal off. Disabling USP18, genetically or with a first-in-class small molecule, could restore interferon's effect and strengthen chemotherapy, radiation, and immunotherapy, with patients who have myeloproliferative neoplasms as the most likely early beneficiaries. Separately, finding metabolic and chromatin vulnerabilities in t(8;21) acute myeloid leukemia could inform targeted treatments for patients who relapse after chemotherapy and currently have poor prognoses.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Mechanistic Targeting of the Type I Interferon Pathway to Improve Efficacy of Cancer Therapies
NIH · Jul 2026 – Jun 2031
Identification of small molecule activators of Type I interferon signaling for cancer treatment
NIH · Jun 2026 – May 2029
Molecular Mechanism of Leukemogenesis involving AML1-ETO
NIH · Jul 2004 – Mar 2027
Closest labs
Golam Mohi
University of Virginia, VA·Medicine & Clinical Research
Determine how loss of PTPN1, a signal-shutting enzyme deleted with chromosome 20q, cooperates with the JAK2V617F mutation to drive myeloproliferative neoplasm progression and bone marrow fibrosis.
Ravindra Majeti
Stanford University, CA·Genetics
Determine how long the pre-leukemic phase lasts in people who progress to acute myeloid leukemia, and whether that duration affects how the disease develops.
Xunlei Kang
University of Missouri-Columbia, MO·Medicine & Clinical Research
Determine how DPP4, a cell-surface enzyme, controls the location, survival and self-renewal of human AML stem cells, using colony-forming assays and mice carrying human AML cells.
The school
University of California-San Diego: 84 labs on PI Pages, $1.9B a year on research, 637 research doctorates a year.
Reach out
A start for your email. Fill in the brackets.