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. 2024 Sep 23:14:1438052.
doi: 10.3389/fonc.2024.1438052. eCollection 2024.

Molecular profiling of pre- and post- 5-azacytidine myelodysplastic syndrome samples identifies predictors of response

Mónica Del Rey González #  1   2 , Sohini Chakraborty #  2 , Jesús María Hernández-Sánchez  1 , María Diez Campelo  3 , Christopher Y Park #  2 , Jesús María Hernández Rivas #  1   3
Affiliations

Molecular profiling of pre- and post- 5-azacytidine myelodysplastic syndrome samples identifies predictors of response

Mónica Del Rey González et al. Front Oncol. .

Abstract

Treatment with the hypomethylating agent 5-azacytidine (AZA) increases survival in high-risk (HR) myelodysplastic syndrome (MDS) patients, but predicting patient response and overall survival remains challenging. To address these issues, we analyzed mutational and transcriptional profiles in CD34+ hematopoietic stem/progenitor cells (HSPCs) before and following AZA therapy in MDS patients. AZA treatment led to a greater reduction in the mutational burden in both blast and hematological responders than non-responders. Blast and hematological responders showed transcriptional evidence of pre-treatment enrichment for pathways such as oxidative phosphorylation, MYC targets, and mTORC1 signaling. While blast non-response was associated with TNFa signaling and leukemia stem cell signature, hematological non-response was associated with cell-cycle related pathways. AZA induced similar transcriptional responses in MDS patients regardless of response type. Comparison of blast responders and non-responders to normal controls, allowed us to generate a transcriptional classifier that could predict AZA response and survival. This classifier outperformed a previously developed gene signature in a second MDS patient cohort, but signatures of hematological responses were unable to predict survival. Overall, these studies characterize the molecular consequences of AZA treatment in MDS HSPCs and identify a potential tool for predicting AZA therapy responses and overall survival prior to initiation of therapy.

Keywords: gene expression; hematopoietic stem/progenitor cells (HSPCs); mutations; myelodysplastic syndrome (MDS); patient survival; prognosis.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Figures

Figure 1
Figure 1
Comprehensive landscape of mutations in the MDS cohort. (A) Dynamics of gene mutations in CD34+ cells during AZA treatment. Genes are represented in rows; each column represents a patient. Dynamics are represented by a color gradient: green/cyan for newly acquire/increasing mutations, cobalt blue for stable mutations, and navy/violent colors for decreasing/disappearing mutations. (B) Proportion of transitions and transversions and how they change after AZA treatment. (C) Graphical representation of transition mutations and how they change after AZA treatment. (D) Ratio between VAF from BMMCs and CD34+ population. Blue plots represent mutations before AZA treatment and orange plots represent mutations after therapy.
Figure 2
Figure 2
Transcriptional analysis of MDS HSPCs in comparison to healthy control CD34+ cells. Pathway analysis of pre- and post-treatment MDS HSPCs in comparison to healthy, age-matched controls.
Figure 3
Figure 3
Transcriptional profiles of MDS patients associated with blast response before AZA treatment. (A) Pathway analysis of blast responders (BL-R) and non-responders (BL-NRs) before treatment with AZA. (B) Expression of LSC-17 genes in MDS HSPCs, based on BL-R and BL-NR gene signature. (C) Immunological pathway analysis of BL-R and BL-NRs before treatment with AZA. (D). Pathway analysis of hematological responders (HEM-R) and non-responders (HEM-NRs) before treatment with AZA.
Figure 4
Figure 4
Transcriptional profiles of pre-/post-AZA treatment MDS HSPCs. (A) Pathways enriched in BL-R and BL-NR samples pre-/post-AZA (B) Cell cycle associated pathways in BL-R and BL-NR samples pre-/post-AZA (C) Pathways enriched in HEM-R and HEM-NR samples pre-/post-AZA.
Figure 5
Figure 5
Kaplan-Meier survival analysis of MDS patients, based on BL-R and BL-NR gene signature (A) Survival analysis of patients, recorded in GSE19429, based on sample classification into blast R-like, or NR-like, according to our blast-R and blast-NR gene signature. (B) Survival analysis of NR-like patients from (A), based on high, or low expression of blast-NR signature. (C) Survival analysis of R-like patients from (A), based on high, or low expression of blast-R signature. (D) Survival analysis of patients recorded in GSE77750, classified as blast-R-like or NR-like, based on our blast-R and blast-NR gene signature.
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