1. Gallagher, Amy

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A recent study has shown a crucial need to improve frontline therapy strategies for treating myelodysplastic syndromes (MDS) (N Engl J Med 2022; doi: 10.1056/NEJMoa2119771). Scientists representing a global collaboration are proposing a strategy for early intervention to enhance treatment outcomes for patients diagnosed with MDS.

MDS; Leukemia. MDS; ... - Click to enlarge in new windowMDS; Leukemia. MDS; Leukemia

The researchers examined the current first-line MDS treatment of the hypomethylating agents (HMA) combination regimen of azacitidine (AZA) and decitabine and its association with the oncofetal protein gene SALL4. The analysis was conducted by a multi-team collaboration of researchers from the Cancer Science Institute of Singapore, Brigham and Women's Hospital (BWH), and Harvard Medical School.


"SALL4 is a gene that is turned on in the embryo and disappears in most adult normal tissues," noted Li Chai, MD, Associate Professor of Pathology at Harvard. The recent study shows that HMAs could result in turning on the "sleeping" gene-an abnormally expressed SALL4 gene.


"In some cases, SALL4 is switched back on in various cancers, including high-risk MDS and leukemia, thus driving tumor development as a cancer gene, ultimately leading to poor survival outcomes for patients, even those in temporary disease remission," she explained. "Abnormally expressed SALL4 can cause MDS."


Methodology & Results

In her work at Harvard, Chai's lab primarily centers on the basic mechanism and biology of MDS, including the discovery of SALL4 as a driver oncogene for the development of MDS/AML. Co-author Maria Teresa Voso, MD, Associate Professor at the University of Rome Tor Vergata in Italy, who has been conducting research in this area, collaborates with Chai in her lab to examine the basic mechanism and biology of MDS.


"This pioneering research is part of an open-label, Phase II, non-randomized, multicenter trial to assess the feasibility of treatment with the hypomethylating agent 5-azacytidine (5-AZA) followed by allogeneic stem cell transplant," Chai explained. "In the study, we used paired bone marrow samples from 25 MDS patients on the BMT-AZA trial, which began in 2010."


She noted the study of SALL4 expression shown in the MDS patients was retrospective, which was discovered when the team realized SALL4 could be reactivated after demethylation, either by a virus such as hepatitis B or a drug such as HMA treatment. "Hep B virus can induce a pseudogene that leads to demethylation of SALL4 and reactivation."


Chai noted the most unexpected finding of the research of MDS patients was the SALL4 upregulation after 4 cycles of AZA treatment in 40 percent of the cases.


"Significantly, patients with SALL4 upregulation had the worst outcome," she said, explaining the results as expressed in p=0.03, median 13.8 months in the SALL4 upregulated versus not reached in the SALL4 downregulated, as studied among the patient group consisting of 17 males and eight females, with the median age of 59.6.


Chai explained that, in 2006, the FDA approved the HMA decitabine injection for treatment of patients with MDS, including previously treated and untreated, de novo, and secondary MDS of all French-American-British subtypes. These include refractory anemia, refractory anemia with ringed sideroblasts-which are normally present in the bone marrow and enter the circulation after maturing into a normal erythrocyte-refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia, as well as intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups.


Driven by the accumulation of two previous research studies in 2006 and 2021, studying the expression of SALL4 associated with the development of MDS and leukemia led to the significant findings of the current research study, specifically the findings under the leadership of Daniel Tenen, MD, Professor at the Harvard Stem Cell Institute, who collaborates with the BWH team.


Future Applications

Although the exact mechanism through which HMAs work is still unknown, the newly established principles support the importance of monitoring SALL4 expression levels in patients receiving HMA therapy. The research teams plan to conduct larger prospective studies to validate their findings and develop low-cost, accurate biomarker kits to monitor SALL4 expression.


"To better help MDS patients, we propose to develop a diagnostic test focused on this gene, study how its activation leads to a poor prognosis, and pursue alternative treatments that take advantage of SALL4's abundance," Chai explained. "Our goal is to be able to predict prognosis of MDS patients on HMA treatment and offer them personalized care."


Chai said her next plan is to create and validate an ultrasensitive test for SALL4. "Simultaneously, we plan to continue our preclinical work on SALL4-targeting treatment," she said.


Through collaborative research across laboratories, the team aims to develop more effective and specific drugs that target SALL4 directly.


Amy Gallagher is a contributing writer.