title: Residual normal stem cells can be detected in newly diagnosed chronic myeloid leukemia patients by a new flow cytometric approach and predict for optimal response to imatinib.
abstract: Insensitivity of chronic myeloid leukemia (CML) hematopoietic stem cells to tyrosine kinase inhibitors (TKIs) prevents eradication of the disease and may be involved in clinical resistance. For improved treatment results more knowledge about CML stem cells is needed. We here present a new flow cytometric approach enabling prospective discrimination of CML stem cells from their normal counterparts within single-patient samples. In 24 of 40 newly diagnosed CML patients residual normal CD34(+)CD38(-) stem cells could be identified by lower CD34 and CD45 expression, lower forward/sideward light scatter and by differences of lineage marker expression (CD7, CD11b and CD56) and of CD90. fluorescent in situ hybridization (FISH) analysis on Fluorescence-activated cell sorting sorted cells proved that populations were BCR-ABL positive or negative and long-term liquid culture assays with subsequent colony forming unit assays and FISH analysis proved their stem cell character. Patients with residual non-leukemic stem cells had lower clinical risk scores (Sokal, Euro), lower hematological toxicity of imatinib (IM) and better molecular responses to IM than patients without. This new approach will expand our possibilities to separate CML and normal stem cells, present in a single bone marrow or peripheral blood sample, thereby offering opportunities to better identify new CML stem-cell-specific targets. Moreover, it may guide optimal clinical CML management.
authors.affiliation: Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands. jjwm.janssen@vumc.nl
authors.forename: J J W M
authors.initials: JJ
authors.lastname: Janssen
authors.forename: W
authors.initials: W
authors.lastname: Deenik
authors.forename: K G M
authors.initials: KG
authors.lastname: Smolders
authors.forename: B J
authors.initials: BJ
authors.lastname: van Kuijk
authors.forename: W
authors.initials: W
authors.lastname: Pouwels
authors.forename: A
authors.initials: A
authors.lastname: Kelder
authors.forename: J J
authors.initials: JJ
authors.lastname: Cornelissen
authors.forename: G J
authors.initials: GJ
authors.lastname: Schuurhuis
authors.forename: G J
authors.initials: GJ
authors.lastname: Ossenkoppele
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000032:analysis; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D005260:Female; D005434:Flow Cytometry / Q000379:methods*; D006801:Humans; D000068877:Imatinib Mesylate; D016130:Immunophenotyping; D017404:In Situ Hybridization, Fluorescence; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000473:pathology*; D010879:Piperazines / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*
chemical_list: D015703:Antigens, CD; D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate