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Cell Architecture Drives MDS and Progression, Could Guide Second-Line Treatment

June 27, 2022

July 2022

The hematopoietic cell architecture in myelodysplastic syndromes (MDS) may have the potential to predict disease progression and guide use of second-line treatment after hypomethylating agent (HMA)-based therapy failure, according to a study in Nature Medicine. Simona Colla, PhD, of the University of Texas MD Anderson Cancer Center in Houston, and colleagues wanted to explore the hematopoietic cells that drive disease evolution in MDS to see whether they could discover vulnerabilities that would help inform therapeutic options.

Current standard of care for MDS is HMA-based therapy. However, the disease eventually becomes resistant to these agents and progresses to secondary acute myeloid leukemia (AML). Patients who experience disease progression to AML have a median survival duration of only four to six months.

Using large patient cohorts, Dr. Colla and colleagues conducted integrative molecular profiling of hematopoietic cells and progenitor cells. They found that MDS hematopoietic cells had two distinct differentiation states that were maintained through the clinical course of the disease and that expanded at progression. These distinct MDS hematopoietic cells activated specific anti-apoptotic regulator BCL-2 or nuclear factor-kappa B-mediated survival pathways.

“The relevance of our study lies in the finding that, despite MDS being highly genetically heterogeneous, the stem cells that originate and maintain the disease after failure to HMA therapy across different patients share oncogenic properties that make them vulnerable to specific therapeutic interventions,” Dr. Colla said.

Researchers conducted preclinical experiments to pharmacologically deplete these pathways’ MDS hematopoietic cells, and they were able to reduce tumor burden.

“Oncogenic mechanisms are cell type-dependent, which means that such interventions will need to be tailored to the architecture of the stem cell compartment in each patient,” Dr. Colla said. “In other words, the take-home message would be that the stem cell hierarchy in patients with MDS can be used as a biomarker to guide the choice of treatment in those who fail conventional therapy and progress to a more aggressive form of the disease.”

Findings from this study support the systematic profiling of the architecture of the stem cell compartment in patients with MDS before a second-line therapy is assigned and set the foundation for the discovery of therapies that specifically target MDS progression-driving stem cells.

“For instance, we have described a group of patients who may obtain significant benefit from therapy with the pro-apoptotic drug venetoclax,” Dr. Colla said.

Dr. Colla and colleagues evaluated outcomes of 21 patients with MDS with blast progression after HMA therapy who were treated with HMAs and venetoclax at MD Anderson Cancer Center. Those patients whose stem cells upregulated BCL-2 achieved improved clinical responses to venetoclax-based therapy. Specifically, they had shorter cumulative time to achieve complete remission and a longer relapse-free survival duration.

“Patients with MDS who fail standard therapies currently have no approved therapeutic alternatives and a very poor prognosis, particularly those whose disease progresses to leukemia,” Dr. Colla said. “The use of the stem cell architecture as a biomarker to inform clinical decisions will allow the selection of patient-tailored second-line therapies, and the personalized use of more efficient stem cell-specific therapeutic alternatives, such as venetoclax, will significantly improve the prognoses of patients with MDS and progressive disease.”

Any conflicts of interest declared by the authors can be found in the original article.


Ganan-Gomez I, Yang H, Ma F, et al. Stem cell architecture drives myelodysplastic syndrome progression and predicts response to venetoclax-based therapy. Nature Medicine. 2022;28:557-567.


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