Similar to AML, tracking major chromosomal abnormalities allowed earlier investigators to establish that clonal hematopoiesis in MDS originated in HSCs. Initially, deletion of the long arm of chromosome 5 (del(5q)) was identified in the HSCs of patients with del(5q)-MDS. Moreover, del(5q) CD34+CD38− cells were shown to possess MDS-initiating potential using in vitro and in vivo stem cell assays. Systems subsequently improved phenotypic identification of HSCs that have allowed investigators to focus on Lin−CD34+CD38−CD90+CD45RA− cells as candidate CSCs in MDS. These studies showed that in patients with del(5q)-MDS, 99% of Lin−CD34+CD38−CD90+CD45RA− cells contained del(5q) and that they were molecularly and functionally distinct from clonally involved GMPs and MEPs. By gene expression profiling and principle component analysis of RNA sequencing data, the three cell populations were shown to be distinctively different, with the Lin−CD34+CD38−CD90+CD45RA− cells selectively expressing genes characteristic of normal HSCs. These candidate stem cells were exclusively able to sustain long-term generation of MDS myeloid pro genitors in vitro that was not observed with GMPs, MEPs, or CMPs. Moreover, patients with del(5q)-MDS were found to have residual del(5q) clones in the CD34+CD38−CD90+ stem cell compartment during clinical remission. Over time, most of these patients experienced expansion of the clone, leading to cytogenetic and clinical progression.

The evidence for an MDS-initiating stem cell is not limited to isolated del(5q)-MDS, which may be a unique disease entity given its distinct clinical features. In fact, recent studies have shown that recur rent driver mutations occur at the HSC level in a broad panel of low to intermediate risk MDS and that the 5q deletion preceded any other identifiable recurrent driver mutations in isolated del(5q)-MDS. The same was observed with SF3B1 mutation-positive MDS that is characterized by ringed sideroblasts, where SF3B1 mutations are thought to be early and potentially initiating events. Targeted screening for mutations of a large number of genes known to be frequently mutated in MDS and other myeloid malignancies has been performed on bulk bone marrow from patients with MDS. After identifying the mutations specific to each patient, the different cell compartments (HSC, GMP, or MEP) were purified and the screen for mutations was repeated. It was hypothesized that if progenitor cells acquired self-renewal capacity, allowing them to persist long enough for the mutations to be responsible for the MDS phenotype, then the mutations would be identifiable in progenitors but not within HSCs. However, all of the mutations in MDS patients have been traced back to the HSC compartment (Lin−CD34+CD38−CD90+CD45RA− cells) and all of the mutations found in the Lin−CD34+CD38−CD90+CD45RA− MDS-initiating cells have also been identified in downstream GMPs and MEPs. These findings suggest that MDS is propagated by a stem cell that develops and acquires mutations at an early stage in the disease.

Interestingly, Chen and colleagues provided evidence for a non linear, parallel manner by which MDS patient HSCs progress to AML. They identified distinct progenitor populations that gave rise to MDS and MDS-related AML. They demonstrated that the dominant AML clone originated from a clone that was included in as pre MDS and/ or MDS HSCs but was undetectable in the MDS blast cells, indicating MDs stem cells are distinct from those that contribute to AML that follow MDS.

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