The Hematologist

March-April 2019, Volume 16, Issue 2

The Cellular Pathway of Leukemic Transformation in MDS: It's the Stem Cells, Stupid!

Alba Rodriguez-Meira, DPhil DPhil Candidate in Medical Sciences
Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
Adam Mead, MD, PhD Professor of Hematology
Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom

Published on: February 19, 2019

Chen J, Kao YR, Sun D, et al. Myelodysplastic syndrome progression to acute myeloid leukemia at the stem cell level. Nat Med. 2019;25:103-110.

Myelodysplastic syndromes (MDS) are malignant hematologic diseases characterized by defective myeloid differentiation and high risk of transformation to secondary acute myeloid leukemia (sAML), which is associated with dismal clinical outcomes. MDS is propagated by rare and distinct MDS stem cells that accumulate somatic mutations. Previous bulk sequencing studies have demonstrated that acquisition of additional genetic and cytogenetic abnormalities correlates with progression of MDS to sAML, but the specific subset of cells in which this clonal evolution occurs has not been identified. Characterizing the cell-of-origin underlying transformation to sAML is essential to understanding the molecular events responsible for leukemic transformation in chronic myeloid malignancies, which will pave the way for early detection and interventions to prevent later disease progression.

Combining high-resolution targeted deep-sequencing of fractionated bone marrow populations and single-cell sequencing, Dr. Jiahao Chen and colleagues characterized the cellular architecture of clonal evolution in seven patients with MDS who progressed to sAML. Previous studies had suggested that sAML evolved from an ancestral MDS subclone that acquired further genetic mutations mostly in a linear and hierarchical fashion.1,2 However, results from Dr. Chen and colleagues suggest that the evolutionary landscape of transformation might be more complex than previously thought.

Targeted sequencing of stem cells and blasts from longitudinal samples revealed that at both the MDS and sAML stages, stem cells were more genetically diverse than blast counterparts in the same patient. Consequently, only a subset of the genetic subclones present in stem cells could be identified in MDS or sAML blast cells analyzed at the bulk level. Subsequent targeted single-cell sequencing of the same populations confirmed that dominant clones identified in MDS blasts and sAML blasts frequently differed within the same patient, but all genetic subclones could be traced back to the stem cell compartment. These results support that genetically distinct subpopulations of stem cells within an individual patient give rise to MDS versus sAML blasts, leading the authors to propose a model of parallel rather than stepwise evolution in the progression to sAML.

Although further functional studies are now needed to elucidate the molecular and functional mechanisms of this process, the model proposed by Dr. Chen and colleagues substantially revises our current understanding of pathways to leukemic transformation in chronic myeloid malignancies. Furthermore, the key finding that genetic heterogeneity can differ markedly in stem cell versus bulk tumor populations has implications more broadly for precision oncology approaches, which typically involve analysis of total tumor populations. This study nicely demonstrated that genetic analysis of fractionated cell populations, including stem cells, can provide additional information that might more accurately predict disease course. Clearly, the challenge is now to analyze larger MDS patient cohorts, including patients without disease transformation, to understand more precisely how genetic heterogeneity of stem cells correlates with risk of disease transformation.

Dr. Chen and colleagues identify previously unrecognized pre-leukemic stem cell heterogeneity in MDS prior to the development of sAML, which underlies disease transformation. Rather than stepwise linear evolution from an ancestral MDS subclone, Dr. Chen and colleagues demonstrate that, in many cases, clonal evolution occurs through selection of pre-existing subclones within the stem cell compartment. This study represents a major step forward toward understanding the evolutionary processes leading to leukemic transformation of MDS and paves the way for clinical pre-leukemic stem-cell monitoring in these patients.

References

  1. Walter MJ, Shen D, Ding L, et al. Clonal architecture of secondary acute myeloid leukemia. N Engl J Med. 2012;366:1090-1098.
  2. Makishima H, Yoshizato T, Yoshida K, et al. Dynamics of clonal evolution in myelodysplastic syndromes. Nat Genet. 2017;49:204-212.

Conflict of Interests

Dr. Mead and Dr. Rodriguez-Meira indicated no relevant conflicts of interest. back to top