Single-cell proteo-transcriptomic profiling reveals altered characteristics of stem and progenitor cells in patients receiving cytoreductive hydroxyurea in early-phase chronic myeloid leukemia
Hana Komic,
Malin S. Nilsson,
Lovisa Wennström,
Tagore Sanketh Bandaru,
Pekka Jaako,
Kristoffer Hellstrand,
Fredrik B. Thorén,
Anna Martner
Affiliations
Hana Komic
TIMM Laboratory at Sahlgrenska Center for Cancer Research, University of Gothenburg, Gothenburg, Sweden; Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Malin S. Nilsson
TIMM Laboratory at Sahlgrenska Center for Cancer Research, University of Gothenburg, Gothenburg, Sweden; Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Lovisa Wennström
Department of Hematology, Sahlgrenska University Hospital, Gothenburg, Sweden
Tagore Sanketh Bandaru
Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Pekka Jaako
Sahlgrenska Center for Cancer Research, Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Kristoffer Hellstrand
TIMM Laboratory at Sahlgrenska Center for Cancer Research, University of Gothenburg, Gothenburg, Sweden; Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Fredrik B. Thorén
TIMM Laboratory at Sahlgrenska Center for Cancer Research, University of Gothenburg, Gothenburg, Sweden; Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Anna Martner
TIMM Laboratory at Sahlgrenska Center for Cancer Research, University of Gothenburg, Gothenburg, Sweden; Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Hydroxyurea (HU) is frequently used in the early phase of chronic myeloid leukemia (CML) to achieve cytoreduction prior to tyrosine kinase inhibitor (TKI) therapy. However, its impact on CML stem and progenitor cells (SPC) remains largely unknown. This study utilized targeted proteo-transcriptomic expression data on 596 genes and 51 surface proteins in 60,000 CD14-CD34+ cells from chronic phase CML patients to determine effects of shortterm HU treatment (4-19 days) on CML SPC. Peripheral blood and bone marrow samples were obtained from 17 CML patients eligible for short-term HU treatment (three patients before and after HU; seven patients before HU; and seven patients after HU) and subjected to single-cell CITE-seq and/or flow cytometry analysis. The analysis revealed enhanced frequencies of hemoglobin-expressing (HBA1, HBA2, HBB) erythroid progenitor cells in blood and bone marrow following HU treatment. In addition, there was an accumulation of cell subsets with S/G2/M phase-related gene and protein expression, likely representing cells arrested in, or progressing slowly through, the cell cycle. The increased frequency of cells in S/G2/M phase after HU was observed already among the most immature leukemic stem cells (LSC), and patients with a high fraction of LSC in the S/G2/M phase showed poor responsiveness to TKI treatment. We conclude that short-term HU treatment entails differentiation of erythroid progenitor cells and alters the characteristics of LSC in CML. The results imply that studies of LSC and progenitor populations in CML should take effects of initial HU therapy into account.
