Harvard Catalyst Profiles

Hypomethylating agent (HMA) drugs are widely used to treat patients with myelodysplastic syndromes (MDS), a type of bone marrow failure and pre-leukemic disorder, around the world, but only about half of the MDS patients respond to HMA treatment. The survival of MDS patients after HMA failure is less than 6 months, many of whom transform to acute leukemia. Based on our study published in New England Journal of Medicine in 2022, we propose that HMA treatment leads to upregulation of the oncogene SALL4, which is the basis for the poor clinical outcome and offers a novel target for designing precision medicine. SALL4 is an oncofetal protein. While loss-of-function studies demonstrate that SALL4 is essential for cancer cell survival, gain-of-function studies demonstrate that induced expression in SALL4 negative cancer cells leads to drug resistance and metastasis. Notably, transgenic SALL4 mice develop MDS and acute myeloid leukemia (AML). Although our data showed that MDS patients on HMA monotherapy with SALL4 upregulation have a poor prognosis, we also demonstrated that upregulation of SALL4 renders the cancer cells dependent on (or “addicted to”) SALL4, and thus more vulnerable to additional, targeted therapy. To better help MDS patients, we propose to develop a SALL4-centerned diagnostic assay (biomarker development, and validation via a prospective clinical cohort), and conduct mechanistic studies on the poor prognosis mediated by elevated SALL4. In addition, we propose to test SALL4-based therapies in cell and animal models. Overall, by completing our proposed studies, we can delineate the mechanism and impact of upregulation of SALL4 by HMA therapy in MDS patients. More importantly, we can provide proof-of-concept, pre-clinical studies on a SALL4-centered therapy based on its known function(s) and mechanism(s) in MDS/AML. In the near future, we plan to translate the knowledge we will gain from these studies into clinical personalized management of MDS patients on HMA therapy. Student will work closely with oncology and transfusion medicine mentors, and can participate in biomarker development and validations, and/or SALL4 targeting drug development. Chai lab: https://chailab.bwh.harvard.edu/ NEJM paper:https://www.nejm.org/doi/full/10.1056/NEJMoa2119771 Contact: Jun Liu (HMS class of 2020, Clinical Fellow at Harvard Medical School, Transfusion Medicine fellow 2023-2024), jliu71@bwh.harvard.edu