Reduced hematopoietic stem cell frequency predicts outcome in acute myeloid leukemia
Autor: | Isabel Hoffmann, Van T. Hoang, Rachel Blume, Anna Marciniak-Czochra, Anna Jauch, Andreas Trumpp, Wenwen Wang, Christoph Lutz, Laura Poisa-Beiro, Borhan R. Saeed, Linda Manta, Tilmann Bochtler, Patrick Wuchter, Simon Raffel, Volker Eckstein, Thomas Stiehl, Anthony D. Ho, Marieke A.G. Essers |
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Rok vydání: | 2017 |
Předmět: |
Male
Acute Myeloid Leukemia 0301 basic medicine Myeloid medicine.medical_treatment Cell Count Hematopoietic stem cell transplantation Biology CXCR4 Disease-Free Survival Article Mice 03 medical and health sciences 0302 clinical medicine Cancer stem cell medicine Animals Humans Hematopoietic Stem Cell Transplantation Hematopoietic stem cell Hematology Hematopoietic Stem Cells Minimal residual disease Survival Rate Leukemia Myeloid Acute Haematopoiesis 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Immunology Heterografts Female Stem cell |
Zdroj: | Haematologica |
ISSN: | 1592-8721 0390-6078 |
DOI: | 10.3324/haematol.2016.163584 |
Popis: | 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. |
Databáze: | OpenAIRE |
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