Identification and Characterization of Stem Cells in Preleukemia and Leukemia

Research output: ThesisDoctoral Thesis (compilation)

Abstract

Hematopoietic stem cells (HSCs) are responsible for the daily and life long production of large numbers of mature blood cells through highly regulated self-renewal and multilineage capabilities. Leukemias on the other hand, are characterized by a clonal, dysregulated, lineage skewed proliferation and impaired differentiation as the result of multiple accumulated genetic events. In acute myeloid leukemia (AML) most leukemic blasts have limited proliferative capacity and it has been shown that a small subpopulation of leukemic stem cells (LSCs) possess self-renewal and extensive proliferative capabilities and are thereby responsible and also sufficient for maintaining the leukemia. Myelodysplastic syndromes (MDS) and polycytemia vera (PCV) are myeloid preleukemic disorders thought to originate in a multipotent but myeloid restricted progenitor based on clonal involvement of erythroid, megakaryocytic, granulocytic but not lymphocytic cells. However, the lack of clonal involvement of mature lymphocytes does not exclude that MDS and PCV originate in normal HSCs, since the transformation events might be incompatible with development along the lymphoid pathway and the normal lymphocytes might rather be produced from residual normal HSCs or long-lived lymphoid progenitors produced prior to the onset of the disease. We have been able, through fluorescence activated cell sorting (FACS) purification, fluorescence in situ hybridization (FISH) clonal evaluation and functional HSC reconstitution assays, to show that MDS and PCV initiating cells have a CD34+CD38-Thy-1+ HSC phenotype, strongly indicating that MDS and PCV originates in normal HSCs. In MDS patients with 5q deletions, the origin in normal HSCs was further supported by multilineage involvement including B lymphoid progenitors and in one case also mature B cells. Acute lymphoblastic leukemia (ALL) with t(12;21) translocation have a fairly good prognosis, given only conventional chemotherapy while ALL with Philadelphia chromosome (Ph+) must be allogeneic stem cell transplanted to obtain cure. Using the same strategy as for MDS and PCV, we could for t(12;21) ALL establish that the CD34+CD38- candidate HSC pool could be subdivided into CD19+ leukemic stem cells and CD19- non-clonal, functionally intact normal HSCs while both populations were leukemic in Ph+ ALL. In addition, little or no residual normal HSC activity could be found in Ph+ ALL indicating that leukemias originating in the HSC compartment might negatively affect residual normal HSC activity, presenting one plausibel explanation for the differential prognosis in these two subgroups of ALL.

Details

Authors
  • Lars Nilsson
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cell and Molecular Biology

Keywords

  • Haematology, extracellulära vätskor, Hematologi, Philadelphia chromosome, acute lymphoblastic leukemia, polycytemia vera, 5q- syndrome, myelodysplastic syndromes, self-renewal, preleukemia, Hematopoietic stem cells, leukemic stem cells, extracellular fluids
Original languageEnglish
QualificationDoctor
Awarding Institution
Supervisors/Assistant supervisor
  • [unknown], [unknown], Supervisor, External person
Award date2004 Sep 21
Publisher
  • Lars Nilsson, BMC B10, KLinikgatan 26, S-221 84 Lund, Sweden,
Print ISBNs91-628-6186-7
Publication statusPublished - 2004
Publication categoryResearch

Bibliographic note

Defence details Date: 2004-09-21 Time: 10:15 Place: Föreläsningssal 1, Centralblocket, Lunds Universitetssjukhus External reviewer(s) Name: Dick, John E. Title: Prof. Affiliation: PhD, Dept of Medical Genetics and Microbiology, Toronto General Research Institute, University of Toronto, Toronto, Canada --- Article: I. Isolation and characterization of hematopoietic progenitor/stem cells in 5q-deleted myelodysplastic syndromes: evidence for involvement at the hematopoietic stem cell level.Nilsson L, Åstrand-Grundström I, Arvidsson I and Jacobsson BBlood. 2000;96:2012-2021. Article: II. Involvement and functional impairment of the CD34+CD38-Thy-1+ hematopoietic stem cell pool in myelodysplastic syndromes with trisomy 8.Nilsson L, Åstrand-Grundström I, Anderson K, Arvidsson I, Hokland P, Bryder D, Kjeldsen L, Johansson B, Hellström-Lindberg E, Hast R and Jacobsen SEW.Blood. 2002;100:259-267. Article: III. Distinct patterns of hematopoietic stem cell involvement in acute lymphoblastic leukemia.Castor A, Nilsson L, Åstrand-Grundström I, Anderson K, Strömbeck B, Garwicz S, Bekassy A, Schmiegelow K, Lausen B, Lehman S, Johansson B, and Jacobsen SEW.Manuscript submitted Article: IV. Identification of polycytemia vera initiating stem cells: Clonal involvement and expansion of the CD34+CD38-Lin-Thy-1+ hematopoietic stem cell compartment.Nilsson L, Åstrand-Grundström I, Strömbeck B, Arvidsson I, Castor A, Anderson K, Kutti J, Hast R, Westin J, Johansson B and Jacobsen SEW.Manuscript submitted. The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Hematopoietic Stem Cell Laboratory (013022012)