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Juvenile Chronic Myelogenous Leukemia Multilineage CD34⁺ Cells: Aberrant Growth and Differentiation Properties

Division of Hematology/Onocology, Department of Pediatrics, and Department of Pediatric Laboratory Medicine, Division of Pathology, Hospital for Sick Children, University of Toronto, Toronto, Canada; Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, USA

Key Words. Juvenile chronic myelogenous leukemia • CD34⁺ cells • Monocyte-macrophage colonies

Correspondence: Dr. Melvin H. Freedman, Division of Hematology/Oncology, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada.

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-), 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 lymphohematopoietic 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-, 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- antibodies and anti-GM-CSF antibodies alone or in combination, and by soluble TNF- 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.

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