Growth factor gene activation and clonal heterogeneity in an autostimulatory myeloid leukemia.
Cell lines were isolated from an in vivo-passaged myelomonocytic leukemia, WEHI-274, that arose in a mouse infected with the Abelson leukemia virus-Moloney leukemia virus complex. Clones were isolated in vitro in the presence or absence of a source of a hemopoietic growth factor, interleukin-3 (IL-3), and were divisible into three distinct classes. All three classes were leukemogenic in vivo. In vitro, the class I clone grew slowly at low cell density but responded with an increased growth rate to IL-3, granulocyte-macrophage colony-stimulating factor (GM-CSF), and autoconditioned medium. Supernatants of these cultures contained a factor with the biological, biochemical, and antigenic properties of IL-3. Class II clones grew better in vitro at low cell densities than did the class I clone and also responded with an increased growth rate to IL-3, GM-CSF, and autoconditional medium but produced GM-CSF rather than IL-3. In contrast, class III clones died in vitro at all cell densities unless exogenous IL-3 or GM-CSF was added. Moreover, they produced no autostimulatory factors. In the class I and class II clones, one allele of the respective IL-3 or GM-CSF gene is rearranged, and in each case, grossly abnormal RNA transcripts of the rearranged gene are present. Neither rearrangements nor abnormal RNA transcripts of the IL-3 or GM-CSF gene were detected in the class III clones. All three classes exhibited a common rearrangement of the c-myb gene, which suggested that all were derived from the one ancestral cell. These experiments demonstrate that two distinct and independent autostimulatory events were involved in the progression of a single disease.
Leslie
K B
KB
Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Victoria, Australia.
Schrader
J W
JW
D000818:Animals; D003001:Cloning, Molecular; D003115:Colony-Stimulating Factors / Q000235:genetics / Q000502:physiology; D005786:Gene Expression Regulation; D015321:Gene Rearrangement; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006133:Growth Substances / Q000235:genetics* / Q000502:physiology; D015151:Immunoblotting; D007377:Interleukin-3 / Q000235:genetics / Q000502:physiology; D007951:Leukemia, Myeloid / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D011519:Proto-Oncogenes; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured
D003115:Colony-Stimulating Factors; D006133:Growth Substances; D007377:Interleukin-3; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D016178:Granulocyte-Macrophage Colony-Stimulating Factor