Cell-Type Specific Mechanisms of Hematopoietic Stem Cell (HSC) Expansion Underpin Progressive Disease in Myelodysplastic Syndromes (MDS) and Provide a Rationale for Targeted Therapies

• Published in: Blood 2018-11, Vol.132 (Supplement 1), p.1798-1798
• Main Authors: Ganan-Gomez, Irene, Alfonso, Ana, Yang, Hui, Santoni, Andrea, Marchica, Valentina, Fiorini, Elena, Montalban-Bravo, Guillermo, Ogoti, Yamini, Manyam, Ganiraju, Jiang, Shan, Bao, Naran, Jackson, Christopher, Rose, Ashley, Kanagal-Shamanna, Rashmi, Bueso-Ramos, Carlos E., Cambò, Benedetta, Giuliani, Nicola, Crugnola, Monica, Konopleva, Marina Y., Clise-Dwyer, Karen, Garcia-Manero, Guillermo, Colla, Simona
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2018-99-116881

The mechanisms of HMA failure in MDS remain unclear, as recent advances in sequencing approaches did not enable the molecular characterization of the cells that survive therapy and drive resistance and disease progression. Here, through combined functional and transcriptomic analyses of highly-purified hematopoietic populations isolated from the BM of 132 MDS patients enrolled in clinical trials of single drug HMA therapy, we show that 2 immunophenotypically and molecularly distinct cell types maintain the disease and expand at progression, and we propose therapeutic approaches to overcome MDS evolution. Unsupervised hierarchical clustering followed by principal component analysis of 101 untreated MDS samples based on the frequency of immunophenotypically defined stem and myeloid progenitor cell populations identified the frequencies of the lymphoid-primed multipotent progenitors (LMPPs) and granulo-monocytic progenitors (GMPs) as the main sources of variation across the samples. Further logistic regression analysis enabled the systematic stratification of the samples in 2 main groups. “CMP pattern” MDS was characterized by the prevalence of common myeloid progenitors (CMPs) in the progenitor compartment while “GMP pattern” MDS was characterized by the increased frequency of GMPs in the progenitors and by increased LMPPs and decreased long-term (LT)-HSC frequencies in the BM (Fig A, B). Functional analysis of the CMPs by immunophenotypic characterization of lineage-primed fractions and colony assays revealed that this population was myeloid-biased only in “CMP pattern” MDS but not in “GMP pattern” MDS, suggesting that 2 distinct hierarchical differentiation routes underlie disease manifestation (Fig C). Further logistic regression analysis of 31 MDS samples from patients with progressive disease showed that whereas “CMP pattern” MDS patients with blast expansion were characterized by a significant increase in the BM frequency of LT-HSCs, “GMP pattern” MDS patients were characterized by the expansion of the LMPPs (Fig D). To investigate the molecular pathways underlying the 2 different hierarchical patterns of progression, we analyzed the transcriptional profiling of the HSCs that selectively expanded in the 2 groups of MDS patients. RNA-Seq analysis revealed that, compared with those isolated from patients at baseline, LT-HSCs isolated from “CMP pattern” MDS patients with blast expansion had significantly upregulated genes involved in promoting cell prolif