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Haematologica. 2017 Sep;102(9):1567-1577. doi: 10.3324/haematol.2016.163584. Epub 2017 May 26.

Reduced hematopoietic stem cell frequency predicts outcome in acute myeloid leukemia.

Author information

1
Department of Medicine V, Heidelberg University, Germany.
2
Institute of Applied Mathematics, Interdisciplinary Center for Scientific Computing (IWR), BIOQUANT, Heidelberg University, Germany.
3
Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany.
4
Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Germany.
5
Clinical Cooperation Unit Molecular Hematology/Oncology, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany.
6
Institute of Human Genetics, Heidelberg University, Germany.
7
German Cancer Consortium (DKTK), Heidelberg, Germany.
8
Department of Medicine V, Heidelberg University, Germany christoph.lutz@med.uni-heidelberg.de.

Abstract

In patients with acute myeloid leukemia and low percentages of aldehyde-dehydrogenase-positive cells, non-leukemic hematopoietic stem cells can be separated from leukemic cells. By relating hematopoietic stem cell frequencies to outcome we detected poor overall- and disease-free survival of patients with low hematopoietic stem cell frequencies. Serial analysis of matched diagnostic and follow-up samples further demonstrated that hematopoietic stem cells increased after chemotherapy in patients who achieved durable remissions. However, in patients who eventually relapsed, hematopoietic stem cell numbers decreased dramatically at the time of molecular relapse demonstrating that hematopoietic stem cell levels represent an indirect marker of minimal residual disease, which heralds leukemic relapse. Upon transplantation in immune-deficient mice cases with low percentages of hematopoietic stem cells of our cohort gave rise to leukemic or no engraftment, whereas cases with normal hematopoietic stem cell levels mostly resulted in multi-lineage engraftment. Based on our experimental data, we propose that leukemic stem cells have increased niche affinity in cases with low percentages of hematopoietic stem cells. To validate this hypothesis, we developed new mathematical models describing the dynamics of healthy and leukemic cells under different regulatory scenarios. These models suggest that the mechanism leading to decreases in hematopoietic stem cell frequencies before leukemic relapse must be based on expansion of leukemic stem cells with high niche affinity and the ability to dislodge hematopoietic stem cells. Thus, our data suggest that decreasing numbers of hematopoietic stem cells indicate leukemic stem cell persistence and the emergence of leukemic relapse.

PMID:
28550184
PMCID:
PMC5685219
DOI:
10.3324/haematol.2016.163584
[Indexed for MEDLINE]
Free PMC Article

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