18 March 2022

US researchers have discovered that treatment resistance in patients with myelodysplastic syndromes (MDS) can be caused by two different types of stem cells. The researchers from University of Texas MD Anderson Cancer Center say their discovery could lead to possible therapeutic approaches that target these cells.

Writing in Nature Medicine, the authors say their study spans preclinical and clinical studies, representing the largest analysis to date of MDS patient samples.

If the findings are further validated in larger clinical trials, the researchers say stem cell profiles of MDS could be considered as a biomarker for guiding the design or choice of secondary lines of therapy. The findings indicate that venetoclax induces the death of stem cells in one of the MDS groups, they added.

Senior study author Simona Colla, associate professor of leukaemia, said: “The majority of MDS cases do not respond to current therapies or relapse. This study provides new insight into what causes therapy failure and disease progression in MDS and possibly provides targeted treatment options for these patients.”

About half of MDS patients who are treated with hypomethylating agents (HMAs), the standard of care, will develop resistance to these drugs and progress to secondary acute myeloid leukaemia. Patients for whom treatment has failed often survive only four to six months and have lower complete response rates to standard therapy.

The research team analysed more than 400 samples from patients with MDS, which were taken at different stages of disease. Using integrative molecular profiling of blood stem cells, they found that HMAs eliminated mature cancer cells but left the stem cells alive, which led to disease relapse.

When they compared bone marrow samples from untreated patients to those of healthy donors, they found MDS samples could be divided into two groups based on the profile of those stem cells.

The samples from one of the MDS groups had an abnormal pattern of increased frequency of common myeloid progenitors (CMP), and the other MDS group had an increased frequency of granulocytic-monocytic progenitors (GMP).

The stem cell populations in both groups sustained the disease during treatment and expanded after HMA therapy failure. This resulted in the disease progressing.

The researchers found the expansions of each of these MDS stem cell types depended on activation of specific signalling pathways unique to each group: the BCL2 survival pathway in the ‘CMP-pattern’ group and NF-κB signalling in the ‘GMP-pattern’ group.

The team targeted the upregulated survival pathways in preclinical models with drugs. They found the treated cells from the CMP-pattern group with the BCL2 inhibitor venetoclax depleted the MDS stem cells in vitro and decreased tumour burden in patient-derived xenograft models.

Similar results were observed when using the NF-κB inhibitor BMS-345541 in cells from the GMP group.

They went on to perform a retrospective analysis of 21 MDS patients with blast progression after treatment with HMA therapy and venetoclax. The team found that venetoclax-based therapy selectively targets leukaemia stem cell populations with the CMP profile.

Researchers observed a significant decrease in stem cells following venentoclax treatment in patients with CMP-pattern disease, but there were no significant changes in patients with GMP pattern MDS.

Dr Irene Ganan-Gomez, lead author of the study, said: “Our study shows both preclinical and clinical evidence that MDS is maintained by two distinct stem cell profiles.

“This research advocates that the stem cell profile of MDS should be considered to determine appropriate therapeutic approaches targeting these cells, particularly for venetoclax-based therapy.”

The authors say further studies are needed to establish whether the immune system contributes to disease remission. In addition, larger prospective trials are needed to determine the selective benefits of the venetoclax treatment in patients with the CMP pattern.

Source: Ganan-Gomez I, Yang H, Ma F, Montalban-Bravo G, Thongon N, Marchica V, Richard-Carpentier G, Chien K, Manyam G, Wang F, Alfonso A, Chen S, Class C, Kanagal-Shamanna R, Ingram JP, Ogoti Y, Rose A, Loghavi S, Lockyer P, Cambo B, Muftuoglu M, Schneider S, Adema V, McLellan M, Garza J, Marchesini M, Giuliani N, Pellegrini M, Wang J, Walker J, Li Z, Takahashi K, Leverson JD, Bueso-Ramos C, Andreeff M, Clise-Dwyer K, Garcia-Manero G, Colla S. (2022) “Stem cell architecture drives myelodysplastic syndrome progression and predicts response to venetoclax-based therapy.” Nature Medicine, doi: 10.1038/s41591-022-01696-4.

Link: https://www.nature.com/articles/s41591-022-01696-4

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