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Effect of the Hemoregulatory Peptide (pEEDCK)2 (pyroGlu-Glu-Asp-Cys-Lys)2 and MIP-1 is Reduced in Bone Marrow Cultures from Patients with Chronic Myeloid Leukemia (CML)

^a Ludwig Boltzmann Institute for Leukemia Research and Hematology, Hanusch Hospital, Vienna, Austria;
^b 3rd Medical Department, Hanusch Hospital, Vienna, Austria;
^c Department of Medicine I, Bone Marrow Transplantation Unit, University of Vienna, Austria;
^d Institute of Medical Chemistry, University of Vienna, Austria;
^e Institute for Cancer Research, University of Vienna, Austria

Key Words. Hemoregulatory peptide • MIP-1 • Long-term bone marrow cultures • Chronic myeloid leukemia

Heidrun Karlic, Ph.D., L. Boltzmann Institute for Leukemia Research, H.Collinstr. 30, A-1140 Vienna, Austria. Telephone: 43-1-91021-2347; Fax: 43-1-9143214; e-mail: heidrun.karlic{at}chello.at

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-1). The present study was designed to analyze differences between the response of normal and leukemic progenitor cells to (pEEDCK)2 or MIP-1. When long-term bone marrow cultures (LTBMCs) were incubated with (pEEDCK)2 or MIP-1 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 (G16, 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-1, thus inducing a downregulation of these factors in bone marrow from CML patients.