Interleukin 1-dependent paracrine granulopoiesis in chronic granulocytic leukemia of the juvenile type.

Abstract

Marrow and peripheral blood cells from nine children with juvenile chronic granulocytic leukemia (JCGL) demonstrated intense (94±16% maximum) spontaneous granulocyte/macrophage colony growth but cells from five children with the adult variety of CGL did not. This unusual pattern of colony growth depended upon a stimulatory protein(s) produced by mononuclear phagocytes. No GM-CSA activity was found in any chromatofocused fraction of JCGL monocyte-conditioned media but an activity that induced GM-CSA in umbilical vein endothelial cells was detected at pI 6.9-7.2. Moreover, the CSA-inducing monokine was neutralized by an anti-IL-i antibody in vitro and, in the one case so tested, the same antibody also inhibited "spontaneous" colony growth. Therefore granulocyte/macrophage colony growth in JCGL is characteristically abnormal and distinguishes JCGL from the adult form of the disease. This abnormality depends upon the production, by mononuclear phagocytes, of IL-1 which, in turn, stimulates the release of high levels of colony stimulating activity by other cells. The high proliferative activity of CFU-GM we found in JCGL patients, and the high levels of GM-CSA found in their serum are compatible with the view that the in vitro abnormality reflects a similar abnormality in vivo.

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

“…Thus, the results suggest that a highly purified population of JCML CD34 + can "self-start" and form colonies in keeping with an autocrine growth pattern. Our data differ from previous studies by others that showed impaired spontaneous JCML colony formation after adherent cell depletion [12,38]. Their studies were performed on light density cells and ours on highly purified CD34 + cells.…”

“…Within these mixed populations of cells, there must be a subpopulation of JCML progenitors that accounts for the abnormal proliferative properties [1][2][3][4][5][6][7][8][9][10][11][12] of the monocyte-macrophage progeny. Our goal is to identify and characterize these JCML progenitors in order to ask fundamental questions about the biology of this aggressive form of leukemia.…”

Juvenile myelomonocytic leukemia and chronic myelomonocytic leukemia

“…Erythroid and megakaryocytic series can be decreased, either due to the granulocytic hypercellularity and subsequent 'crowding out' phenomenon or due to cytokine suppression. 14,29 If the clinician is able to obtain blood before the need for red blood cell transfusions, a hemoglobin electrophoresis can be useful in helping to establish the diagnosis, as greater than 50% of JMML patients will demonstrate a reversion to fetal red blood cell characteristics, including (1) increased levels of hemoglobin F, even when corrected for age, (2) low carbonic anhydrase levels and (3) expression of the i antigen. 30 It should be emphasized that elevated fetal hemoglobin levels are not necessary for a diagnosis of JMML, due to the fact that at least one-third of confirmed JMML diagnoses have normal fetal hemoglobin levels.…”

“…In the 1980s, it was most commonly known as juvenile chronic myelogenous leukemia, but other names ascribed to this disease in the past included juvenile chronic granulocytic leukemia, chronic and subacute myelomonocytic leukemia, CMML of childhood, infantile monosomy 7 and monosomy 7 syndrome. [10][11][12][13][14][15] Some argued that it should be classified as a childhood form of MDS. 16 But, similar to 'adult-type' CMML, this disease clearly had some characteristics of an MPD.…”

FANCA and FANCC modulate TLR and p38 MAPK–dependent expression of IL-1β in macrophages

“…22 Activation of TLR pathways in macrophages induces production of other inflammatory cytokines, including interleukin 1b (IL-1b), [23][24][25] which is known to promote tumor progression and metastasis. 26,27 Expression of IL-1b, like TNF-a, is known to be dependent on the activity of the global stress responsive p38 mitogen-activated protein kinase (MAPK) signal transduction pathway. 28 Therefore, in light of our prior studies and the work of others confirming that TNF-a is a potent endogenous suppressor of normal hematopoietic progenitor and stem cell activity in mice, [11][12][13][14][15] we reasoned that FA marrow progenitors and stem cells might also be hypersensitive to IL-1b and that TLR activation might induce the overproduction of both TNF-a and IL-1b by FA mononuclear phagocytes.…”