Effect of the hemoregulatory peptide (pEEDCK)2 (pyroGlu-Glu-Asp-Cys-Lys)2 and MIP-1alpha is reduced in bone marrow cultures from patients with chronic myeloid leukemia (CML).

Abstract

The granulocyte-derived hemoregulatory peptide pyroGlu-Glu-Asp-Cys-Lys = pEEDCK is known to keep hematopoietic cells quiescent. When oxidized to its dimeric form (pEEDCK)2, it activates growth of hematopoietic progenitors in association with stroma-derived cytokines. (pEEDCK)2 has a Cys-Cys motif which is also a typical feature of the macrophage inflammatory protein (MIP-1alpha). The present study was designed to analyze differences between the response of normal and leukemic progenitor cells to (pEEDCK)2 or MIP-1alpha. When long-term bone marrow cultures (LTBMCs) were incubated with (pEEDCK)2 or MIP-1alpha and/or cytokines, the stimulatory effect on colony-forming units-granulocyte/erythroid/macrophage/megakaryocyte of LTBMC from chronic myeloid leukemia (CML) patients was less than 50% compared to LTBMC from healthy humans. No difference in oncogene expression could be observed in LTBMC from CML patients regarding reduction of Philadelphia chromosome-associated transcription of the BCR-ABL gene. With respect to the expression of growth and differentiation-associated genes (Galpha16, 5-lipoxygenase, phospholipaseA2, c-kit, and CD34), which were analyzed from LTBMC by semiquantitative reverse transcriptase-polymerase chain reaction, the same transcription rate was observed in CML patients and healthy donors. However, two isoforms of a key enzyme of oxidative metabolism, carnitine palmitoyltransferase (CPT1A and CPT1B), showed 50-fold higher expression rates in LTBMC cells of healthy donors compared to CML patients. It is known that a decrease in oxidative metabolism is associated with an increase in redox equivalents in malignancy. This might result in a reduction of disulphide bonds in (pEEDCK)2 or MIP-1alpha, thus inducing a downregulation of these factors in bone marrow from CML patients.

• Authors: H Karlic, N Louda, M Pfeilstöcker, F Keil, A Lohninger, E Pittermann, J Paukovits
• Journal: Stem cells (Dayton, Ohio) (Stem Cells) Vol. 19 Issue 4 Pg. 321-8 ( 2001) ISSN: 1066-5099 [Print] England
• PMID: 11463952 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chemokine CCL3
• Chemokine CCL4
• Cytokines
• Growth Inhibitors
• Macrophage Inflammatory Proteins
• Oligopeptides
• hemoregulatory peptide 5b
• Pyrrolidonecarboxylic Acid

Topics

• Animals
• Bone Marrow Cells (drug effects, physiology)
• Cells, Cultured
• Chemokine CCL3
• Chemokine CCL4
• Colony-Forming Units Assay
• Cytokines (pharmacology)
• Growth Inhibitors (pharmacology)
• Hematopoietic Stem Cells (drug effects, physiology)
• Humans
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (physiopathology)
• Macrophage Inflammatory Proteins (pharmacology)
• Mice
• Oligopeptides (pharmacology)
• Pyrrolidonecarboxylic Acid (analogs & derivatives)