leptin and Leukemia--Myeloid--Acute

Leptin, the product of obese gene, is a secreting protein that exerts multiple biological functions by binding to its receptor. Leptin regulates nutrient intake and metabolism, and is secreted from adipocytes, which occupy most of the bone marrow cavity and constitute the microenvironment. Leptin not only plays an important role in the control of the proliferation and differentiation of normal primitive hematopoietic cells, but it also stimulates the growth and viability of leukemic cells. Leukemic cells of some patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia, and chronic myeloid leukemia also express the leptin receptor. Furthermore, leptin also stimulates leukemic cell growth in vivo by promoting angiogenesis. These findings suggest the possibility that leptin and its receptor play roles in the pathophysiology of leukemia, and blockage of leptin binding to its receptor might have potential therapeutic benefits in the treatment of certain leukemias. This review discusses the biological characteristics of leptin and its receptor, the relation of leptin and its receptor with normal hematopoiesis, the relation of leptin and its receptor with AML and so on.

Topics: Animals; Hematopoietic System; Humans; Leptin; Leukemia, Myeloid, Acute; Receptors, Leptin

Idiopathic non-clonal cytopenia (ICUS) and clonal cytopenia (CCUS) are common in the elderly population. While these entities have similar clinical presentations with peripheral blood cytopenia and less than 10% bone marrow dysplasia, their malignant potential is different and the biological relationship between these disorders and myeloid neoplasms such as myelodysplastic syndrome (MDS) is not fully understood. Aberrant DNA methylation has previously been described to play a vital role in MDS and acute myeloid leukemia (AML) pathogenesis. In addition, obesity confers a poorer prognosis in MDS with inferior overall survival and a higher rate of AML transformation. In this study, we measured DNA methylation of the promoter for the obesity-regulated gene LEP, encoding leptin, in hematopoietic cells from ICUS, CCUS and MDS patients and healthy controls. We investigated whether LEP promoter methylation is an early event in the development of myeloid neoplasms and whether it is associated with clinical outcome.. We found that blood cells of patients with ICUS, CCUS and MDS all have a significantly hypermethylated LEP promoter compared to healthy controls and that LEP hypermethylation is associated with anemia, increased bone marrow blast percentage, and lower plasma leptin levels. MDS patients with a high LEP promoter methylation have a higher risk of progression, shorter progression-free survival, and inferior overall survival. Furthermore, LEP promoter methylation was an independent risk factor for the progression of MDS in a multivariate Cox regression analysis.. In conclusion, hypermethylation of the LEP promoter is an early and frequent event in myeloid neoplasms and is associated with a worse prognosis.

Topics: Aged; Anemia; Clonal Hematopoiesis; DNA Methylation; Humans; Leptin; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Obesity

Weight loss and metabolic activity influence outcome after allogeneic stem cell transplantation (alloSCT). This study evaluates pre-conditioning Leptin, a peptide hormone involved in metabolism and immune homeostasis, as a prognostic factor for survival, relapse and non-relapse mortality (NRM) following alloSCT. Leptin serum levels prior to conditioning were determined in a cohort of patients transplanted for various hematologic malignancies (

Topics: Hematopoietic Stem Cell Transplantation; Humans; Leptin; Leukemia, Myeloid, Acute; Recurrence; Retrospective Studies; Transplantation, Homologous

Obesity enhances the risk of developing myelodysplastic syndromes. However, the effect of obesity on survival is unclear. Obese people present with monocytosis due to inflammatory signals emanating from obese adipose tissue. We hypothesized that obesity-induced myelopoiesis would promote the transition of myelodysplastic syndrome to acute myeloid leukemia and accelerate mortality in obesity. Obese Ob/Ob mice or their lean littermate controls received a bone marrow transplant from NUP98-HOXD13 transgenic mice, a model of myelodysplastic syndrome. The metabolic parameters of the mice were examined throughout the course of the study, as were blood leukocytes. Myeloid cells were analyzed in the bone, spleen, liver and adipose tissue by flow cytometry halfway through the disease progression and at the endpoint. Survival curves were also calculated. Contrary to our hypothesis, transplantation of NUP98-HOXD13 bone marrow into obese recipient mice significantly increased survival time compared with lean recipient controls. While monocyte skewing was exacerbated in obese mice receiving NUP98-HOXD13 bone marrow, transformation to acute myeloid leukemia was not enhanced. Increased survival of obese mice was associated with a preservation of fat mass as well as increased myeloid cell deposition within the adipose tissue, and a concomitant reduction in detrimental myeloid cell accumulation within other organs. The study herein revealed that obesity increases survival in animals with myelodysplastic syndrome. This may be due to the greater fat mass of Ob/Ob mice, which acts as a sink for myeloid cells, preventing their accumulation in other key organs, such as the liver.

Topics: Animals; Bone Marrow; Bone Marrow Transplantation; Disease Models, Animal; Homeodomain Proteins; Leptin; Leukemia, Myeloid, Acute; Mice; Mice, Transgenic; Myelodysplastic Syndromes; Myeloid Cells; Nuclear Pore Complex Proteins; Obesity; Survival Rate; Transcription Factors

The impact of nutritional status on outcome of allogeneic stem cell transplantation (alloSCT) is controversial. This study investigates the influence of pretransplant weight loss and serologic indicators of nutritional homeostasis on relapse and death of acute myeloid leukemia (AML) after alloSCT.. Pretransplant weight loss along with serum levels of total serum protein (TSP), albumin, C-reactive protein, and leptin were collected retrospectively in a training cohort (n = 149) and correlated with clinical outcome. Metabolic risk groups were defined and tested in an independent validation cohort (n = 167).. We identified pretransplant weight loss and TSP as strong independent predictors of relapse and death. Patients in the metabolic high-risk group (low TSP and weight loss) had an increased risk for relapse (P = 0.0002) and death (P = 0.002), but a similar risk for acute graft-versus-host disease. Weight loss coincided with reduced pretransplant serum leptin levels. The adverse influence of weight loss and high metabolic risk on relapse and overall survival could be confirmed in the validation cohort and similarly in patients with less than or more than 5% blasts before alloSCT. Multivariate analysis of both cohorts revealed a hazard ratio for relapse of 7.78 (2.59-23.36, P = 0.0003) in the metabolic high risk group.. Altered nutritional homeostasis before alloSCT correlates with recurrence of AML after transplantation. Studies addressing pretransplant nutritional interventions to reduce AML relapse rates are warranted.

Topics: Blood Proteins; Body Mass Index; Hematopoietic Stem Cell Transplantation; Humans; Leptin; Leukemia, Myeloid, Acute; Nutritional Status; Recurrence; Retrospective Studies; Transplantation, Homologous; Weight Loss

Mesenchymal stromal cells (MSCs) are a major component of the leukemia bone marrow (BM) microenvironment. Connective tissue growth factor (CTGF) is highly expressed in MSCs, but its role in the BM stroma is unknown. Therefore, we knocked down (KD) CTGF expression in human BM-derived MSCs by CTGF short hairpin RNA. CTGF KD MSCs exhibited fivefold lower proliferation compared with control MSCs and had markedly fewer S-phase cells. CTGF KD MSCs differentiated into adipocytes at a sixfold higher rate than controls in vitro and in vivo. To study the effect of CTGF on engraftment of leukemia cells into BM, an in vivo model of humanized extramedullary BM (EXM-BM) was developed in NOD/SCID/IL-2rg(null) mice. Transplanted Nalm-6 or Molm-13 human leukemia cells engrafted at a threefold higher rate in adipocyte-rich CTGF KD MSC-derived EXM-BM than in control EXM-BM. Leptin was found to be highly expressed in CTGF KD EXM-BM and in BM samples of patients with acute myeloid and acute lymphoblastic leukemia, whereas it was not expressed in normal controls. Given the established role of the leptin receptor in leukemia cells, the data suggest an important role of CTGF in MSC differentiation into adipocytes and of leptin in homing and progression of leukemia.

Topics: Adipocytes; Animals; Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation; Cell Cycle; Cell Differentiation; Cell Proliferation; Cell Separation; Chemokine CXCL12; Connective Tissue Growth Factor; Down-Regulation; Gene Knockdown Techniques; Humans; Leptin; Leukemia; Leukemia, Myeloid, Acute; Mesenchymal Stem Cells; Mice; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Adipocytokines was stated to exert biological effect on tumor cells. Two adipokines, leptin and adiponectin in particular, have come to be recognized for their influence on tumor biology including leukemia. The prognostic effect of leptin and adiponectin concentrations in acute leukemia patients remains to be identified. This study was conducted on 80 acute leukemia patients: 35 acute myeloid leukemia (AML), 45 acute lymphoid leukemia (ALL), and 20 controls of matched age and sex. Leptin and adiponectin were assayed by enzyme-linked immunosorbent assay at diagnosis. Serum leptin levels were significantly higher in ALL patients, and significantly lower in AML patients when compared with normal controls (P = 0.01, P = 0.04 respectively). On the other hand, serum adiponectin levels were significantly lower in AML and ALL patients as compared with normal controls (P = 0.00 for both). No significant differences exist regarding body mass index between acute leukemia patients and normal controls (P > 0.05). Correlation studies revealed that there were significant negative correlations between serum adiponectin levels and bone marrow (BM) blast cells and serum lactic dehydrogenase (sLDH) in acute leukemia groups (r 0.542, P < 0.01, r 0.699, P < 0.001, respectively). Regarding serum leptin levels there were positive significant correlations with BM blast cells (r 0.74, P < 0.01), total WBC counts (r = 0.59, P < 0.05), sLDH (r 0.738, P < 0.01) in ALL group; and significant negative correlations with BM blast cells (r 0.542, P < 0.01) and sLDH in the AML group. Adipocytokines may represent a new non-invasive biomarker in acute leukemia patients. Estimation of adiponectin and leptin serum levels at acute leukemia diagnosis could also be considered as a prognostic marker, which will be used in acute leukemia stratification.

Topics: Adiponectin; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Case-Control Studies; Female; Humans; Leptin; Leukemia, Myeloid, Acute; Male; Middle Aged; Prognosis

Leptin acts as a growth factor in normal cells as well as in various types of cancer cells. We investigated the effects of leptin on human acute myelogenous leukemia (AML) cells. Leptin stimulated the proliferation of HEL cells through the phosphorylation of STAT3 and ERK1/2. The blocking of STAT3 phosphorylation with the specific inhibitor, AG490, significantly reduced leptin-induced ERK1/2 phosphorylation and cellular proliferation, whereas the blocking of ERK1/2 activation by the specific ERK1/2 inhibitor, PD98059, did not affect the STAT3 phosphorylation or leptin-induced proliferation in HEL cells. Furthermore, knockdown of leptin receptor (OB-R) expression with stealth RNA interference (RNAi) reduced the leptin-induced proliferation of HEL cells and also significantly attenuated leptin-induced STAT3 and ERK1/2 activation. These results suggest that leptin promotes AML cell growth by activating STAT3 and MAPK, although not directly dependent on ERK.

Topics: Cell Proliferation; Flavonoids; HL-60 Cells; Humans; K562 Cells; Leptin; Leukemia, Myeloid, Acute; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Phosphorylation; Protein Kinase Inhibitors; Receptors, Leptin; Recombinant Proteins; RNA Interference; Signal Transduction; STAT3 Transcription Factor; Tyrphostins

Several studies have implicated leptin in the pathophysiology of neoplasias. We investigated the direct effect of leptin on malignant hematopoietic tissue that included: primary acute myeloid leukemia (AML) cells, leukemic cell lines and bone marrow biopsies from multiple myeloma (MM) patients. PBMC, T-cells, B-cells and monocytes from healthy subjects served as controls. We defined the patterns of OB-R isoform expression in AML cells and leukemic cell lines in comparison to control cells by RT-PCR. rLeptin upregulated the expression of OB-R and endogenous leptin in AML blasts and certain cell lines but not in control cells. Cytometric Bead Array analysis of pro- and anti-inflammatory cytokines showed that rleptin upregulates IL-6 secretion by AML cells, various cytokines by the leukemic cell lines tested and IL-10 secretion by control PBMC, contributed by monocytes. Western immunoblotting revealed that the effect of rleptin was independent of JAK-2/phospho-JAK-2 protein levels. Finally, MM biopsies stained positive for leptin and, to a lesser extend, OB-R. Immunoreactivity was confined mostly to the nucleus of the myeloma cells. Normal myelocytes, promyelocytes and megakaryocytes stained weakly positive, and erythroid cells were constantly negative. We propose that the leptin/OB-R system is strongly and directly involved in supporting the growth of hematopoietic malignancies.

Topics: B-Lymphocytes; Blotting, Western; Cell Line, Tumor; Cells, Cultured; Cytokines; Electrophoresis, Polyacrylamide Gel; Gene Expression Profiling; Gene Expression Regulation; Humans; Immunohistochemistry; Leptin; Leukemia, Myeloid, Acute; Monocytes; Protein Isoforms; Receptors, Leptin; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction; T-Lymphocytes

Leptin is a regulator of fat metabolism that is synthesized in adipocytes and released into circulation. The serum levels of leptin are, therefore, correlated with body fat mass and show a wide variation in healthy individuals. Leptin may have an additional indirect effect on leukemic hematopoesis. We investigated serum leptin levels with enzyme-linked immunosorbent assays in 14 acute myeloblastic leukemia (AML) patients before and after chemotherapy and compared the results with that of the levels determined 14 healthy controls. We found no significant difference between leptin levels before and after chemotherapy and control group. Therefore, serum leptin level should not be used as a diagnostic marker in acute leukemia patients. However, the possibility of regional leptin production by leukemia blasts in bone marrow stroma creates a high local concentration of leptin within bone marrow microenvironment and systemic leptin level in combination with local leptin production may affect leukemic hematopoesis.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Case-Control Studies; Female; Humans; Leptin; Leukemia, Myeloid, Acute; Male; Middle Aged

Leptin is an adipocyte-derived hormone regulating energy homeostasis and body weight. Leptin also plays a role in hematopoiesis, cell cycle regulation, and in oncogenesis. The leptin receptor is a single transmembrane protein belonging to the superfamily of cytokine receptors, structurally related to the hemopoietin receptor family. The aim of the study was to evaluate bone marrow and peripheral blood leptin level and frequency of distribution of leptin receptor gene polymorphism Gln223Arg in children with acute leukemia. The examined group included 92 children with acute leukemia (83 ALL and 9 AML) and 39 non-leukemic control children. Leptin level was measured by ELISA method at the day of leukemia diagnosis. Genomic DNA was isolated with the use of a column method and the genotyping of DNA sequence variation was carried out by the restriction enzyme analysis of PCR - amplified DNA. The samples were then electrophoresed on 2.5% agarose gel. Leptin level in leukemic children was lower than in healthy children. Bone marrow leptin level was significantly lower than that in the blood in leukemic children with ALL-T and AML. An analysis of frequency distribution of the Gln233Arg polymorphism in the leptin receptor gene in leukemic children showed lack of differences between the patients and controls. There was no difference in the genotype frequencies between the leukemic AML and ALL groups either. The results indicate a possible relation between the leptin level and leukemia development in children. The effectory effect of the hormone seems not related to Gln223Arg polymorphism of its receptor.

Topics: Adolescent; Bone Marrow; Child; Child, Preschool; Humans; Infant; Leptin; Leukemia; Leukemia, Myeloid, Acute; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Receptors, Leptin

Leptin, the adipocyte hormone, and its receptor have been implicated in the differentiation/proliferation of hematopoietic cells. Given that the deregulated expression of a variety of growth factors and/or their receptors has been implicated in the pathogenesis of certain leukemias, we aimed to characterize the potential differences in the expression pattern of the two major leptin receptor transcript variants in peripheral blood mononuclear cells (PBMC) between different hematologic malignancies. Using RT-PCR and Southern blotting, we compared the expression levels of the two major leptin receptors, the longest (OB-R(L)) and the shortest (OB-R(S)) splice variants, in PBMC from patients with myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), healthy individuals and two human hematopoietic cell lines (HL-60 and K562). Expression of the OB-R(S) transcript clearly exceeded that of OB-R(L) in all patients and controls and in the HL-60 cells, but this was reversed in the K562 cell line. However, the expression of the OB-R(L) was significantly lower in MDS compared to controls and tended to be so in AML, while OB-R(S) tended to be higher in MDS and AML patients compared to controls, but this difference was not significant. Serum leptin levels and circulating soluble leptin receptor levels were slightly but not significantly higher in AML and MDS. These alterations in the expression of the leptin receptor isoforms in MDS and AML patients could suggest a potential role of leptin and its signaling in hematopoietic malignancies, which requires further examination.

Topics: Adult; Aged; Alternative Splicing; Female; Gene Expression Regulation, Leukemic; HL-60 Cells; Humans; K562 Cells; Leptin; Leukemia, Myeloid, Acute; Leukocytes, Mononuclear; Male; Middle Aged; Myelodysplastic Syndromes; Protein Isoforms; Receptors, Cell Surface; Receptors, Leptin; Signal Transduction

The cytogenetic abnormalities and the response to induction therapy have been regarded as the most important prognostic parameters in acute myelogenous leukemia (AML) patients. Recent studies have demonstrated that internal tandem duplications and specific D-835 point mutations of the Flt3 gene, as well as the angioregulatory phenotype represent additional adverse prognostic factors. The aim of the study was to investigate possible associations between genetic abnormalities, differentiation status and angioregulatory phenotype in native human AML blasts.. Native AML blasts derived from consecutive patients were cultured in vitro and concentrations of angioregulatory molecules determined in the supernatants.. Most patients released at least two different angioregulatory mediators. Pro-angiogenic interleukin 8 (IL8) was released at relatively high levels for most patients, many of these patients showed additional release of pro-angiogenic vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF). High release of anti-angiogenic IL12 was associated with high release of pro-angiogenic IL8 and VEGF. Furthermore, patients with D-835 mutations showed increased IL12 release, whereas patients with normal karyotype had decreased HGF release. Myelomonocytic differentiation was associated with IL18 release and CD34 expression with low IL12 release.. Our results suggest that native human AML blasts have a pro-angiogenic phenotype. Although the investigated genetic abnormalities are associated with variation in the in vitro release of angioregulators, these differences are relatively small and do not quantitatively involve the most important IL8 release. It therefore seems unlikely that this phenotypic variation can explain the prognostic impact of the genetic abnormalities.

Topics: Adult; Aged; Aged, 80 and over; Antigens, CD34; Cell Differentiation; Collagen; Endostatins; Endothelial Growth Factors; Female; Fibroblast Growth Factor 2; fms-Like Tyrosine Kinase 3; Hepatocyte Growth Factor; Humans; Intercellular Signaling Peptides and Proteins; Interleukin-12; Interleukin-18; Interleukin-8; Karyotyping; Leptin; Leukemia, Myeloid, Acute; Lymphokines; Male; Middle Aged; Neovascularization, Pathologic; Peptide Fragments; Phenotype; Point Mutation; Prognosis; Proto-Oncogene Proteins; Receptor Protein-Tyrosine Kinases; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Leptin alone and in combination with other cytokines has a stimulatory effect on proliferation of leukaemic cells. This effect may be due to prevention of apoptosis of progenitor cells or upregulation of specific receptors on leukaemic precursors that make them more responsive to stimuli. This work investigates the relationship between serum leptin level, serum interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) in acute leukaemic patients. The relationship to blood cell counts, haemoglobin and response to chemotherapy was also investigated. The study included 25 acute leukaemic male patients [15 acute myeloid leukaemia (AML) and 10 acute lymphoblastic leukaemia (ALL)] and 15 age and sex matched healthy controls. All were subjected to thorough history taking, clinical examination, complete blood picture, hepatic and renal function tests and determination of serum leptin, IL-6 and VEGF levels. In addition, patients were subjected to bone marrow aspiration, cytochemistry and immunophenotyping study and serum leptin assay after chemotherapy. Serum leptin level showed statistically significant elevation only in AML group (p<0.01). This elevation was unrelated to the presence of extramedullary infiltration or response to chemotherapy and correlated only with body mass index (p<0.05). In ALL, the mean serum leptin level was insignificantly different from the controls. In both AML and ALL, there was no significant difference in serum leptin level before and after treatment. Statistically significant elevation of IL-6 and VEGF, uncorrelated with serum leptin level was detected in AML patients when compared with the controls. No correlation was found between serum leptin level and any of the studied haematological parameters. It is concluded that the release of leptin, IL-6 and VEGF may be regulated by different mechanisms leading to diversity in clinical features of the disease.

Topics: Adolescent; Adult; Aged; Case-Control Studies; Humans; Interleukin-6; Leptin; Leukemia, Myeloid, Acute; Male; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Vascular Endothelial Growth Factor A

Leptin receptors can be expressed by acute myelogenous leukemia (AML) cells, but the functional effects of leptin on native AML blasts have not been characterized in detail. We investigated systemic leptin levels in AML patients and in vitro effects of leptin on cultured AML blasts.. Serum leptin levels were compared for patients with untreated AML and healthy controls. Native AML blasts were derived from a large group of consecutive patients, and effects of leptin on proliferation (suspension cultures and colony formation), constitutive cytokine secretion, differentiation and apoptosis regulation were assayed in vitro.. Systemic leptin levels were decreased in patients with untreated AML, and leptin levels in acute leukemia patients were not altered during severe chemotherapy-induced cytopenia and complicating febrile neutropenia. In vitro studies demonstrated that leptin increased AML blast release of interleukin (IL) 1beta, IL6, tumor necrosis factor (TNF) alpha and granulocyte-macrophage colony-stimulating factor (GM-CSF). This enhancing effect showed no correlation with CD34 expression and was not dependent on the presence of serum, induction of differentiation or alteration of caspase 3 activity with decreased in vitro apoptosis. Leptin also increased spontaneous AML blast proliferation, whereas divergent effects on blast proliferation were observed in the presence of exogenous cytokines. The in vitro effects were usually observed at concentrations exceeding the systemic levels.. Our results suggest that systemic leptin levels alone do not have a major influence on native AML blasts, but the systemic levels in combination with local leptin release in the bone marrow may affect the functional characteristics of these cells.

Topics: Adult; Aged; Aged, 80 and over; Apoptosis; Case-Control Studies; Cell Culture Techniques; Cell Differentiation; Cytokines; Female; Humans; Leptin; Leukemia, Myeloid, Acute; Leukocytes, Mononuclear; Male; Middle Aged