Clonal dominance of chronic myelogenous leukemia is associated with diminished sensitivity to the antiproliferative effects of neutrophil elastase

Abstract

Clinical observations suggest that in chronic myelogenous leukemia (CML), the Philadelphia chromosome (Ph+) clone has a growth advantage over normal hematopoiesis. Patients with CML have high levels of neutrophil elastase, which has recently been shown to antagonize the action of granulocyte-colony-stimulating factor (G-CSF) and other growth factors. We therefore compared the effect of elastase on the growth of normal and CML progenitor cells. In 10-day suspension cultures of normal or CML CD34+ cells supplemented with G-CSF, stem cell factor (SCF), and granulocyte macrophage-colony-stimulating factor (GM-CSF), CML cells had diminished sensitivity to the growth inhibitory effect of elastase. When equal numbers of CML and normal CD34+ cells were cocultured for 10 days, there was no change in the relative proportions of normal and leukemic cells (measured by fluorescence in situ hybridization [FISH] or flow cytometry). However, when elastase was added, CML cells predominated at the end of the culture period (78% vs 22% with 1 microg/mL and 80% vs 20% with 5 microg/mL elastase). CML neutrophils substituted effectively for elastase in suppressing the proliferation of normal CD34+ cells, but this effect was abrogated by serine protease inhibitors. These results suggest that elastase overproduction by the leukemic clone can change the growth environment by digesting growth factors, thereby giving advantage to Ph+ hematopoiesis.

Motility, proliferation, and egress to the circulation of human AML cells are elastase dependent in NOD/SCID chimeric mice

“…Elastase produced by chronic myelogenous leukemia (CML) neutrophils preferentially suppresses normal hematopoiesis. 20 Elastase can cleave G-CSF and its receptor, abolishing its proliferative effect on normal human CD34 ϩ progenitor cells. 21,22 Moreover, proteolytic processing by elastase was recently suggested to play an important role in the development of leukemogenic processes.…”

Human neutrophil elastase is not a target for therapy in chronic myeloid leukaemia

“…1 The efforts to decrease the risk of graft-versus-host disease (GVHD) as a major cause of transplant-related mortality by depleting T cells from the graft resulted in an increased incidence of CML relapse. 2 These observations revealed that donor T cells representing the mediators of GVHD are also capable of inducing therapeutic HNE plasma levels pre-IM treatment. n Po0.05, nnn Po0.005 with respect to normal plasma or marrow control.…”

“…2 Elafin is a naturally occurring inhibitor of HNE, and can restore normal proliferation when added to mixed CML/normal cell cultures (El-Ouriaghli et al Blood 2003; 102: 230a; abstract). We sought to determine whether HNE levels are elevated in CML bone marrow (BM) and peripheral blood (PB) samples taken pre-and post-treatment with the tyrosine kinase inhibitor, imatinib mesylate (IM) and to determine any correlation with disease stage.…”

Characterization of immunologic properties of a second HLA-A2 epitope from a granule protease in CML patients and HLA-A2 transgenic mice

“…1 These 2 proteins are aberrantly expressed in human myeloid leukemias such as chronic myeloid leukemia (CML). 2 Overexpression of PR3 may be important in maintaining a leukemia phenotype because inhibition of PR3 synthesis by PR3-antisense oligonucleotides halts cell division and drives differentiation of the HL-60 promyelocytic leukemia cell line. 3 HNE is also overexpressed in leukemia patients and has been shown to suppress tumorigenic hematopoietic progenitors.…”

“…3 HNE is also overexpressed in leukemia patients and has been shown to suppress tumorigenic hematopoietic progenitors. 2 Thus, both proteins are attractive as vaccine targets.…”