MDS HSCs display two separate differentiation patterns that expand at disease progression.
Major Finding: MDS HSCs display two separate differentiation patterns that expand at disease progression.
Concept: Activation of BCL-2 and NF-κB survival pathways mediate the CMP and GMP patterns, respectively.
Impact: These two distinct differentiation states can serve as biomarkers to guide second-line therapy after HMA failure.
Hypomethylating agents (HMA) represent the current standard of care for myelodysplastic syndromes (MDS), with a majority of patients demonstrating a clinical response to these therapies. However, resistance eventually occurs, leading to development of secondary acute myeloid leukemia. Disease progression has been shown to be mediated by MDS cells residing in the hematopoietic stem cell (HSC) compartment, but what role these cells play in therapy failure and disease evolution is not currently known. To address this issue, Ganan-Gomez and colleagues sought to determine the biological mechanisms involved in HMA therapy resistance and disease evolution and identified two differentiation patterns in 123 untreated patients with MDS, one defined as a common myeloid progenitor (CMP) pattern, with the other being a granulocytic–monocytic progenitor (GMP) pattern. Investigation into the effect of HMA therapy on these two differentiation patterns revealed that these altered patterns persisted during treatment, with the CMP and GMP cell populations being depleted by 5-azacytidine treatment, while the long-term and short-term HSCs survived, suggesting that disease relapse and progression after HMA treatment is mediated by MDS stem cells. Analysis of gene expression revealed upregulation of cell proliferation and survival genes such as BCL-2 in the CMP pattern, whereas an increase in genes involving the NF-κB pathway were observed in the GMP pattern. Treatment of each group with pharmacologic inhibitors of BCL-2 (ABT-199) or an NF-κB inhibitor (BMS-345541) showed altered survival in only the CMP-pattern and GMP-pattern groups, respectively, supporting the notion that inhibition of the specific upregulated survival pathways in each group can induce HSC death. Furthermore, venetoclax treatment exhibited a clinical response in patients with CMP-pattern MDS, with a reduction in time to complete remission as well as longer relapse-free survival. Overall, this study demonstrates two cellular states with distinct upregulation of two different survival pathways that contribute to HMA failure and MDS disease progression, indicating the use of therapeutic approaches to specifically target these vulnerabilities to improve patient outcome.
Note:Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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