leptin and Leukemia--Myelogenous--Chronic--BCR-ABL-Positive

The aim of the present study was to determine serum levels of neutrophil gelatinase-associated lipocalin (NGAL) and leptin in patients with chronic myeloid leukemia (CML) at diagnosis and after imatinib therapy when patients achieved a complete molecular remission. The study was conducted on 22 patients with CML in the chronic phase and 10 healthy subjects. The median serum NGAL levels in CML patients at diagnosis were significantly higher compared to age-matched controls. After imatinib therapy, all patients achieved complete molecular remission and NGAL levels decreased and were found significantly lower with respect to the baseline. No significant correlations were found between NGAL levels and other disease parameters. Before imatinib therapy, the median blood leptin levels were not significantly different from those of controls. After therapy with imatinib, all patients in molecular remission presented an increase in leptin levels. Future research is eagerly awaited as it may demonstrate the real role of NGAL and leptin in the onset and progression of CML.

Topics: Acute-Phase Proteins; Adult; Aged; Antineoplastic Agents; Benzamides; Female; Follow-Up Studies; Humans; Imatinib Mesylate; Leptin; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Lipocalin-2; Lipocalins; Male; Middle Aged; Piperazines; Proto-Oncogene Proteins; Pyrimidines; Remission Induction

Chronic myelogenous leukemia (CML), a myeoloproliferative disorder, is characterized by the presence of the fusion gene BCR-ABL in hematopoietic cells. Leptin, considered a link between cancer and obesity, has been reported to be actively involved in hemopoiesis and pathophysiology of CML. There are few and conflicting reports about the status of serum leptin levels and recently alteration in leptin has been reported due to imatinib mesylate.. Leptin and CRP were estimated in 30 (male: 20; female: 10) newly diagnosed and confirmed MBCR- ABL p210 positive CML patients before and after 3 months of therapy by commercial enzyme linked immunosorbent assays. Leptin levels were compared with 30 (male: 20; female: 10) age matched healthy controls accounting for the differences due BMI and gender.. Leptin/BMI ratio was significantly raised in both male and female chronic phase patients as compared to controls (p < 0.001, p = 0.048) and accelerated phase patients as compared to controls (males, p < 0.001; females, p < 0.001). The normal gender difference and dependence on BMI was lost in patients. In patients, who failed to achieve hematological baseline, leptin/BMI was higher only in male patients (p = 0.012). Leptin/BMI also correlat- ed with TLC and blast percentage (TLC, R2 = 0.412, p = 0.001; Blast %, R2 = 0.408, p < 0.001). There was no correlation between leptin and CRP levels. Levels decreased significantly after complete hematological remission in both males and females (p = 0.001, p = 0.028). Levels after 3 months of imatinib therapy were significantly higher than controls in all patients not in remission (males, p < 0.001; females, p = 0.018) but only in male patients in re- mission (p = 0.002).. Leptin levels were increased in CML patients. The findings suggest a possible role of leptin in patho- genesis of CML or disease progression independent of inflammatory state or reactionary rise. Imatinib itself may increase leptin levels, and, as leptin plays an active role in the pathophysiology of CML, this conflicting scenario needs further investigation. Alterations in leptin need to be investigated cautiously accounting for confounding and differences due to BMI and gender.

Topics: Adult; Antineoplastic Agents; Benzamides; Biomarkers, Tumor; Body Mass Index; Case-Control Studies; Confounding Factors, Epidemiologic; Enzyme-Linked Immunosorbent Assay; Female; Fusion Proteins, bcr-abl; Genetic Predisposition to Disease; Humans; Imatinib Mesylate; Leptin; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Middle Aged; Phenotype; Piperazines; Protein Kinase Inhibitors; Pyrimidines; Sex Factors; Time Factors; Treatment Outcome; Up-Regulation

It is suspected that bone marrow (BM) microenvironmental factors may influence the evolution of chronic myeloid leukaemia (CML). In this study, we postulated that adipocytes and lipids could be involved in the progression of CML. To test this hypothesis, adipocytes were co-cultured with two BCR-ABL positive cell lines (PCMDS and K562). T cell (Jurkat) and stroma cell (HS-5) lines were used as controls. In the second set of experiments, leukemic cell lines were treated with stearic, oleic, linoleic or α-linolenic acids in presence or absence of leptin. Survival, proliferation, leptin production, OB-R isoforms (OB-Ra and OB-Rb), phosphoinositide 3-kinase (PI3k) and BCL-2 expression have been tested after 24h, 48h and 72h of treatment. Our results showed that adipocytes induced a decrease of CML proliferation and an increase in lipid accumulation in leukemic cells. In addition, CML cell lines induced adipocytes cell death. Chromatography analysis showed that BM microenvironment cells were full of saturated (SFA) and monounsaturated (MUFA) fatty acids, fatty acids that protect tumor cells against external agents. Stearic acid increased Bcl-2 expression in PCMDS, whereas oleic and linoleic acids had no effects. In contrast, α-linolenic acid decreased the proliferation and the survival of CML cell lines as well as BCL-2 and OB-R expression. The effect of α-linolenic acids seemed to be due to PI3K pathway and Bcl-2 inhibition. Leptin production was detected in the co-culture medium. In the presence of leptin, the effect of α-linolenic acid on proliferation, survival, OB-R and BCl-2 expression was reduced.

Topics: Adipocytes; alpha-Linolenic Acid; Apoptosis; Bone Marrow; Caspases; Cell Communication; Cell Line, Tumor; Cell Proliferation; Cell Survival; Coculture Techniques; Culture Media; Enzyme Activation; Fibroblasts; Humans; Leptin; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Lipid Metabolism; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Receptors, Leptin; Signal Transduction