Juvenile chronic myelogenous leukemia multilineage CD34+ cells: aberrant growth and differentiation properties.
Juvenile chronic myelogenous leukemia (JCML) is a hematologic malignancy of monocyte-macrophage lineage in which leukemic progression is mediated in an autocrine manner by tumor necrosis factor (TNF-alpha), GM-CSF and possibly other growth factors. Cytogenetic data showing involvement of both erythroid and monocyte-macrophage lineages in the JCML leukemic clone, as well as an observed episode of B-lineage lymphoid blast crisis in JCML, has strengthened the thesis for a lympho-hematopoietic pluripotent stem cell origin for the disorder. To study this further, JCML CD34+ cells from bone marrow (BM) or spleen from six newly diagnosed patients were isolated and cultured in clonogenic assays with combinations of recombinant cytokines. Compared to control CD34+ cells, JCML cells from all patients showed an aberrant growth pattern restricted almost exclusively to the monocyte-macrophage lineage. Most of the clonogenic activity was seen in a subsorted population of CD34+, HLA-Dr- cells. Additionally, an exaggerated growth response to minute doses of GM-CSF that had no effect on control cells was observed with JCML CD34+ cells. Recloning ("self-renewal") of JCML CD34+ cells was also strongly promoted by GM-CSF. JCML colonies also formed spontaneously in the absence of exogenous cytokines but were augmented by GM-CSF, interleukin 1 and TNF-alpha, the latter feature not seen with control CD34+ cells from normal BM. The abnormal spontaneous growth pattern of CD34+ JCML cells could be suppressed directly in vitro by anti-TNF-alpha antibodies and anti-GM-CSF antibodies alone or in combination, and by soluble TNF-alpha receptors (sTNF-R:Fc), consistent with the notion that JCML CD34+ cells are stimulated by both cytokines in an autocrine manner. In malignant CD34+ cells from one patient, the cytogenetic marker monosomy 7 proved leukemic involvement of monocyte-macrophage, erythroid and B-lymphoid lineages. We conclude that CD34+ JCML cells of multilineage potential exhibit excessive and aberrant monocyte-macrophage colony formation, a property that was previously observed in JCML progenitors found in light density cell fractions. Thus, within the CD34+ cellular compartment is a subpopulation of JCML "stem" cells that accounts for the abnormal leukemic proliferative activity in this disease.
Freedman
M H
MH
Department of Pediatrics, Hospital for Sick Children, University of Toronto, Ontario, Canada.
Hitzler
J K
JK
Bunin
N
N
Grunberger
T
T
Squire
J
J
D000328:Adult; D018952:Antigens, CD34 / Q000737:chemistry*; D001854:Bone Marrow Cells; D002448:Cell Adhesion / Q000187:drug effects; D002675:Child, Preschool; D002999:Clone Cells / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000097:blood*; D008297:Male; D013154:Spleen / Q000166:cytology; D013234:Stem Cells / Q000737:chemistry / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D018952:Antigens, CD34; D007377:Interleukin-3; D014409:Tumor Necrosis Factor-alpha; D016178:Granulocyte-Macrophage Colony-Stimulating Factor