RESUMO
TMEM127 is an endosome-associated tumor suppressor gene in pheochromocytomas, neuroendocrine tumors that can co-occur with renal cell carcinomas (RCCs). TMEM127 loss leads to increased mTOR signaling. However, the spectrum of tumors with TMEM127 mutation and how TMEM127 and mTOR interact in tumorigenesis remains unknown. Here, we report that germline TMEM127 mutations occur in RCCs and that some mutant proteins, unlike wild-type (WT) TMEM127, fail to cooperate with activated early endosomal GTPase, Rab5, to inhibit mTOR signaling. Tmem127-null mouse embryonic fibroblasts (MEFs) are deficient in generating early-to-late hybrid endosomes upon constitutive Rab5 activation, a defect rescued by WT, but not mutant, TMEM127. This endosomal dysfunction results in diminished mTOR colocalization with Rab5-positive vesicles. Conversely, active, lysosomal-bound mTOR is increased in Tmem127-null MEFs, which also display enhanced lysosomal biogenesis. Our data map the tumor-suppressive properties of TMEM127 to modulation of mTOR function in the endolysosome, a feature that may contribute to both pheochromocytoma and RCC pathogenesis.
Assuntos
Carcinoma de Células Renais/metabolismo , Endossomos/metabolismo , Proteínas de Membrana/metabolismo , Animais , Carcinoma de Células Renais/genética , Linhagem Celular , Endossomos/genética , Células HeLa , Humanos , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Microscopia de Fluorescência , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Pheochromocytomas (PCCs) and paragangliomas (PGLs) are catecholamine-secreting tumors of neural crest origin. Once collectively known as the '10% tumor', based on the frequency of inherited forms of the disease, they are now referred to as the '10-gene tumor', based on the number of susceptibility genes identified to date. Most familial cases of pheochromocytoma and/or paraganglioma and 10-20% sporadic cases carry germline mutations in VHL, RET, NF1, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, or MAX. The finding of somatic mutations in VHL and RET in an additional 10-15% of tumors has brought the proportion of all patients with PCC and/or PGL due to a genetic disruption in these genes to approximately one half. These findings impact on the clinical management of patients. The diversity in the genetic etiology has transcription correlates, which are reflected in the 2 main transcription signatures underlying these mutations: a pseudohypoxic cluster (VHL and SDH gene mutation carriers) and a cluster rich in kinase receptor signaling and protein translation pathways (RET, NF1, TMEM127 and MAX mutation carriers). Recognition of these clusters offers clues to better understand tumor pathogenesis as well as a rationale for the development of targeted therapies. In this report we provide an overview of the transcription-based classification of PCCs and PGLs, an update on the more recently identified susceptibility genes and an outline of current gaps in this research field as well as challenges for the coming years.
Assuntos
Neoplasias das Glândulas Suprarrenais/genética , Paraganglioma/genética , Feocromocitoma/genética , Neoplasias das Glândulas Suprarrenais/congênito , Animais , Predisposição Genética para Doença , Humanos , Mutação , Paraganglioma/congênito , Feocromocitoma/congênitoRESUMO
Pheochromocytomas and paragangliomas are catecholamine-secreting tumors of neural crest origin caused by germline mutations in at least six distinct genes. This genetic heterogeneity has provided a rich source for both the discovery and functional characterization of new tumor-related genes. However, the genetic repertoire of these tumors is still not fully known, and current evidence points to the existence of additional pheochromocytoma susceptibility genes. Here, the unique contributions of three hereditary models of pheochromocytoma that can advance our knowledge of the disease pathogenesis are presented. The first model, loss of succinate dehydrogenase (SDH) function, illustrates how SDHB, C, or D mutations, components of the energy metabolism pathway, serve as a unique system to explore the pervasive metabolic shift of cancer cells towards glycolysis as a source of energy (also known as the Warburg effect) in contrast to the characteristic oxidative phosphorylation of normal cells. In the second model, mechanisms of tumorigenesis distinct from classical pheochromocytoma susceptibility genes are discussed in the context of a novel putative suppressor of neural crest-derived tumors, the KIF1B beta gene. Finally, NF1 loss is highlighted as a valuable study model to investigate the cell lineage selectivity of the Egln3-mediated developmental apoptotic defect of chromaffin precursor cells. Results from these studies may offer clues to understand the tissue specificity of hereditary pheochromocytoma syndromes. These distinct hereditary disease models illustrate how genetic-driven progress has the potential to narrow current gaps in our knowledge of pheochromocytoma and paraganglioma pathogenesis.
Assuntos
Neoplasias das Glândulas Suprarrenais/genética , Variação Genética , Feocromocitoma/genética , Neoplasias das Glândulas Suprarrenais/enzimologia , Humanos , Mutação , Feocromocitoma/enzimologia , Succinato Desidrogenase/genética , Succinato Desidrogenase/metabolismoAssuntos
Proteínas de Drosophila , Neoplasias das Glândulas Endócrinas/genética , Aberrações Cromossômicas , Clonagem Molecular , Éxons , Ligação Genética , Humanos , Mutação , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas Proto-Oncogênicas , Proteínas Proto-Oncogênicas c-ret , Receptores Proteína Tirosina QuinasesRESUMO
Pheochromocytomas are neural crest-derived tumors that occur mostly sporadically, but may also be part of inherited syndromes. The molecular pathogenesis of sporadic pheochromocytomas remains unknown. Recently, the susceptibility gene for familial paraganglioma syndrome, a disorder embryologically related to pheochromocytomas, was characterized and shown to encode the small subunit of succinate dehydrogenase (SDHD), which is part of the mitochondrial complex II. This complex regulates oxygen-sensing signals. Importantly, hypoxic signals also appear to be related to the pathogenesis of pheochromocytomas associated with von Hippel-Lindau syndrome. We sequenced the entire coding region of the SDHD gene in a series of pheochromocytomas. Although we did not find mutations in the gene, we identified a new intronic single nucleotide polymorphism in 15% of the samples (g.97739A-->G). We also confirmed the existence of a sequence highly homologous to the SDHD complementary DNA in chromosome 1p34--36, a region commonly deleted in pheochromocytomas. Full analysis of this sequence revealed a heterozygous single base substitution in 70% of our samples that was also present in the germline. This sequence does not appear to be transcribed and is probably a processed pseudogene. Therefore, despite its chromosomal location, it is unlikely that this sequence is a target of loss of heterozygosity in pheochromocytomas. In conclusion, mutations of the SDHD gene are not a common event in this series of sporadic pheochromocytomas. The existence of SDHD pseudogenes should be considered when analyzing complementary DNA-based samples.
Assuntos
Neoplasias das Glândulas Suprarrenais/genética , Predisposição Genética para Doença/genética , Proteínas de Membrana/genética , Paraganglioma/genética , Feocromocitoma/genética , Sequência de Aminoácidos/genética , Sequência de Bases/genética , Cromossomos Humanos Par 1/genética , Humanos , Dados de Sequência Molecular , Polimorfismo Genético/genética , Pseudogenes/genética , Succinato Desidrogenase , Síndrome , Transcrição GênicaRESUMO
The pheochromocytomas are an important cause of secondary hypertension. Although pheochromocytoma susceptibility may be associated with germline mutations in the tumor-suppressor genes VHL and NF1 and in the proto-oncogene RET, the genetic basis for most cases of nonsyndromic familial pheochromocytoma is unknown. Recently, pheochromocytoma susceptibility has been associated with germline SDHD mutations. Germline SDHD mutations were originally described in hereditary paraganglioma, a dominantly inherited disorder characterized by vascular tumors in the head and the neck, most frequently at the carotid bifurcation. The gene products of two components of succinate dehydrogenase, SDHC and SDHD, anchor the gene products of two other components, SDHA and SDHB, which form the catalytic core, to the inner-mitochondrial membrane. Although mutations in SDHC and in SDHD may cause hereditary paraganglioma, germline SDHA mutations are associated with juvenile encephalopathy, and the phenotypic consequences of SDHB mutations have not been defined. To investigate the genetic causes of pheochromocytoma, we analyzed SDHB and SDHC, in familial and in sporadic cases. Inactivating SDHB mutations were detected in two of the five kindreds with familial pheochromocytoma, two of the three kindreds with pheochromocytoma and paraganglioma susceptibility, and 1 of the 24 cases of sporadic pheochromocytoma. These findings extend the link between mitochondrial dysfunction and tumorigenesis and suggest that germline SDHB mutations are an important cause of pheochromocytoma susceptibility.
Assuntos
Predisposição Genética para Doença/genética , Mutação/genética , Paraganglioma/enzimologia , Paraganglioma/genética , Feocromocitoma/enzimologia , Feocromocitoma/genética , Succinato Desidrogenase/genética , Sequência de Aminoácidos , Sequência de Bases , Análise Mutacional de DNA , Feminino , Mutação em Linhagem Germinativa/genética , Haplótipos/genética , Humanos , Perda de Heterozigosidade/genética , Masculino , Dados de Sequência Molecular , Mutação de Sentido Incorreto/genética , Linhagem , Subunidades Proteicas , Proto-Oncogene Mas , Alinhamento de Sequência , Succinato Desidrogenase/química , Succinato Desidrogenase/metabolismoRESUMO
Various genes have been identified to play a role in the pathogenesis of follicular thyroid tumors. Cowden syndrome is the only known familial syndrome with an increased risk of both follicular thyroid adenoma (FA) and carcinoma (FTC). Germline mutations in the tumor suppressor gene PTEN, which encodes a dual-specificity phosphatase, have been found in up to 80% of patients with Cowden syndrome suggesting a role of PTEN in the pathogenesis of follicular thyroid tumors. Although somatic intragenic mutations in PTEN, which maps to 10q23.3, are rarely found in follicular tumors, loss of heterozygosity (LOH) of markers within 10q22-24 occurs in about 25%. Recently, another phosphatase gene, MINPP1, has been localized to 10q23.3. MINPP1 has the ability to remove 3-phosphate from inositol phosphate substrates, a function that overlaps that of PTEN. Because of this overlapping function with PTEN and the physical location of MINPP1 to a region with frequent LOH in follicular thyroid tumors, we considered it to be an excellent candidate gene that could contribute to the pathogenesis of follicular thyroid tumors. We analyzed DNA from tumor and corresponding normal tissue from 23 patients with FA and 15 patients with FTC for LOH and mutations at the MINPP1 locus. LOH was identified in four malignant and three benign tumors. One of these FTCs with LOH was found to harbor a somatic c.122C > T or S41L mutation. We also found two germline sequence variants, c.809A > G (Q270R) and IVS3 + 34T > A. The c.809A > G variant was found in only one patient with FA but not in patients with FTC or normal controls. More interestingly, IVS3 + 34T > A was found in about 15% of FA cases and normal controls but not in patients with FTC. These results suggest a role for MINPP1 in the pathogenesis of at least a subset of malignant follicular thyroid tumors, and MINPP1 might act as a low penetrance predisposition allele for FTC.
Assuntos
Adenoma/genética , Carcinoma/genética , Cromossomos Humanos Par 10/genética , Variação Genética , Mutação , Monoéster Fosfórico Hidrolases/genética , Neoplasias da Glândula Tireoide/genética , Proteínas Supressoras de Tumor , Mapeamento Cromossômico , Humanos , Perda de Heterozigosidade , PTEN Fosfo-HidrolaseRESUMO
For many years, it has been thought that the chromosome region 10q22-24 includes one or more genes that appear to play a role in several human malignancies. PTEN is a new tumor suppressor gene encoding a dual-specificity phosphatase that was cloned simultaneously by three groups (Li & Sun 1997, Li et al. 1997, Steck et al. 1997), two of which used a positional cloning approach to identify genes in chromosome 10 (Li et al. 1997, Steck et al. 1997). While several protein kinases have been implicated as oncogenes, and phosphatases have long been known frequently to antagonize their function, there has been no direct demonstration of the role of phosphatases in tumor development (Myers & Tonks 1997). PTEN characterization as a bona fide tumor suppressor gene has confirmed that a deficient phosphatase activity can lead to cancer, as detailed by studies that are described below.
Assuntos
Genes Supressores de Tumor , Monoéster Fosfórico Hidrolases/genética , Proteínas Supressoras de Tumor , Animais , Apoptose , Cromossomos Humanos Par 10 , Clonagem Molecular , Humanos , Camundongos , Camundongos Knockout , Mutação , PTEN Fosfo-Hidrolase , Monoéster Fosfórico Hidrolases/química , Monoéster Fosfórico Hidrolases/fisiologia , Transdução de SinaisRESUMO
Somatic mutations in mtDNA have recently been identified in colorectal tumours. Studies of oncocytic tumours have led to hypotheses which propose that defects in oxidative phosphorylation may result in a compensatory increase in mitochondrial replication and/or gene expression. Mutational analysis of mtDNA in thyroid neoplasia, which is characterised by increased numbers of mitochondria and is also one of the most common sites of oncocytic tumours. has been limited to date. Using the recently developed technique of two-dimensional gene scanning, we have successfully examined 21 cases of thyroid tumours, six cases of non-neoplastic thyroid pathology, 30 population controls, nine foetal thyroid tissues and nine foetal tissues of non-thyroid origin, either kidney or liver. We have identified three different somatic mutations (23%) in papillary thyroid carcinomas. In addition, we have found significant differential distributions of mtDNA sequence variants between thyroid carcinomas and controls. Interestingly, these variants appear to be more frequent in the genes which encode complex I of the mitochondrial electron transport chain compared to normal population controls. These findings suggest first, that somatic mtDNA mutations may be involved in thyroid tumorigenesis and second, that the accumulation of certain non-somatic variants may be related to tumour progression in the thyroid.
Assuntos
Carcinoma Papilar/genética , DNA Mitocondrial/genética , Mutação , Neoplasias da Glândula Tireoide/genética , Adenoma/genética , Estudos de Casos e Controles , DNA de Neoplasias/genética , Variação Genética , Humanos , Dados de Sequência Molecular , NADH Desidrogenase/genética , Glândula Tireoide/embriologia , Glândula Tireoide/patologiaRESUMO
PTEN/MMAC1/TEP1, a tumor suppressor gene, is frequently mutated in a variety of human cancers. Germ-line mutations of phosphatase and tensin homolog, deleted on chromosome ten (PTEN) are found in two inherited hamartoma tumor syndromes: Cowden syndrome, which has a high risk of breast, thyroid, and other cancers; and Bannayan-Zonana syndrome, a related disorder. PTEN encodes a phosphatase that recognizes both protein substrates and phosphatidylinositol-3,4,5-triphosphate. The lipid phosphatase activity of PTEN seems to be important for growth suppression through inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. We established clones with stable PTEN expression controlled by a tetracycline-inducible system to examine the consequences of increased levels of wild-type and mutant PTEN expression in a well-characterized breast cancer line, MCF-7. When we overexpressed PTEN in MCF-7, growth suppression was observed, but only if PTEN phosphatase activity is preserved. The initial growth suppression was attributable to G1 cell cycle arrest, whereas subsequent growth suppression was attributable to a combination of G1 arrest and cell death. Of note, the decrease in Akt phosphorylation preceded the onset-of suppression of cell growth. Treatment of MCF-7 cells with wortmannin, a PI3K inhibitor, caused cell growth inhibition in a way similar to the effects of overexpression of PTEN in this cell. In general, the inverse correlation between PTEN protein level and Akt phosphorylation was found in a panel of breast cancer cell lines. Therefore, PTEN appears to suppress breast cancer growth through down-regulating PI3K signaling, which leads to the blockage of cell cycle progression and the induction of cell death, in a sequential manner.
Assuntos
Neoplasias da Mama/genética , Morte Celular/genética , Fase G1/genética , Proteínas de Neoplasias/fisiologia , Monoéster Fosfórico Hidrolases/fisiologia , Proteínas Serina-Treonina Quinases , Proteínas Supressoras de Tumor , Androstadienos/farmacologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/fisiopatologia , Divisão Celular/genética , Inibidores Enzimáticos/farmacologia , Feminino , Genes Supressores de Tumor/fisiologia , Humanos , Proteínas de Neoplasias/genética , PTEN Fosfo-Hidrolase , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Monoéster Fosfórico Hidrolases/genética , Fosforilação , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-akt , Transfecção , Células Tumorais Cultivadas , WortmaninaRESUMO
Germline mutations in PTEN, encoding a dual-specificity phosphatase on 10q23.3, cause Cowden syndrome (CS), which is characterized by a high risk of breast and thyroid cancers. Loss of heterozygosity of 10q22-24 markers and somatic PTEN mutations have been found to a greater or lesser extent in a variety of sporadic component and noncomponent cancers of CS. Among several series of sporadic breast carcinomas, the frequency of loss of flanking markers around PTEN is approximately 30 to 40%, and the somatic intragenic PTEN mutation frequency is <5%. In this study, we analyzed PTEN expression in 33 sporadic primary breast carcinoma samples using immunohistochemistry and correlated this to structural studies at the molecular level. Normal mammary tissue had a distinctive pattern of expression: myoepithelial cells uniformly showed strong PTEN expression. The PTEN protein level in mammary epithelial cells was variable. Ductal hyperplasia with and without atypia exhibited higher PTEN protein levels than normal mammary epithelial cells. Among the 33 carcinoma samples, 5 (15%) were immunohistochemically PTEN-negative; 6 (18%) had reduced staining, and the rest were PTEN-positive. In the PTEN-positive tumors as well as in normal epithelium, the protein was localized in the cytoplasm and in the nucleus (or nuclear membrane). Among the immunostain negative group, all had hemizygous PTEN deletion but no structural alteration of the remaining allele. Thus, in these cases, an epigenetic phenomenon such as hypermethylation, -ecreased protein synthesis or increased protein degradation may be involved. In the cases with reduced staining, 5 of 6 had hemizygous PTEN deletion and 1 did not have any structural abnormality. Finally, clinicopathological features were analyzed against PTEN protein expression. Three of the 5 PTEN immunostain-negative carcinomas were also both estrogen and progesterone receptor-negative, whereas only 5 of 22 of the PTEN-positive group were double receptor-negative. The significance of this last observation requires further study.
Assuntos
Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Monoéster Fosfórico Hidrolases/biossíntese , Proteínas Supressoras de Tumor , Anticorpos Monoclonais , Especificidade de Anticorpos , Western Blotting , Mama/metabolismo , Mama/patologia , Neoplasias da Mama/genética , Carcinoma Ductal de Mama/genética , Cromossomos Humanos Par 10/genética , Feminino , Marcadores Genéticos , Humanos , Hiperplasia/metabolismo , Imuno-Histoquímica , Perda de Heterozigosidade , Pessoa de Meia-Idade , PTEN Fosfo-Hidrolase , Monoéster Fosfórico Hidrolases/genética , Monoéster Fosfórico Hidrolases/imunologia , Receptores de Estrogênio/biossíntese , Receptores de Progesterona/biossínteseRESUMO
Although the two major familial forms of pheochromocytomas, multiple endocrine neoplasia type 2 and von-Hippel-Lindau disease (VHL), have been associated with mutations of the RET and VHL genes, respectively, the molecular pathogenesis of sporadic pheochromocytomas is largely unknown. Recently, a putative tumor suppressor gene has been identified, CUL2, whose product has been shown to interact with the VHL tumor suppressor. To examine whether CUL2 plays a role in pheochromocytoma pathogenesis, we analyzed a series of 26 distinct tumor samples for mutations in the whole coding region of this gene. There were no somatic pathogenic mutations in CUL2, except for 1 sporadic tumor that had a hemizygous gene deletion. We also found 3 novel polymorphisms in the gene. One of these variants, IVS5-6C/T, as well as another previously described one, c.2057G/A, were overrepresented among the pheochromocytoma patients compared to that in a control population (P < 0.005 and P < 0.01, respectively). Although our findings suggest that CUL2 does not play a major role in the pathogenesis of pheochromocytomas, it is still unknown whether epigenetic mechanisms are involved in its inactivation in VHL-associated tumors. Furthermore, the potential role for the overrepresented alleles in the pheochromocytoma group requires further investigation.
Assuntos
Neoplasias das Glândulas Suprarrenais/genética , Alelos , Proteínas de Transporte/genética , Proteínas de Ciclo Celular/genética , Proteínas Culina , Feocromocitoma/genética , Polimorfismo de Fragmento de Restrição , Doença de von Hippel-Lindau/genética , Adolescente , Adulto , Criança , Feminino , Homozigoto , Humanos , Perda de Heterozigosidade , Masculino , Pessoa de Meia-Idade , Mutação , Polimorfismo Conformacional de Fita Simples , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de DNARESUMO
Glial cell line-derived neurotrophic factor (GDNF) plays a key role in the control of vertebrate neuron survival and differentiation in both the central and peripheral nervous systems. GDNF preferentially binds to GFRalpha-1 which then interacts with the receptor tyrosine kinase RET. We investigated a panel of 36 independent cases of mainly advanced sporadic brain tumours for the presence of mutations in GDNF and GFRalpha-1. No mutations were found in the coding region of GDNF. We identified six previously described GFRalpha-1 polymorphisms, two of which lead to an amino acid change. In 15 of 36 brain tumours, all polymorphic variants appeared to be homozygous. Of these 15 tumours, one also had a rare, apparently homozygous, sequence variant at codon 361. Because of the rarity of the combination of homozygous sequence variants, analysis for hemizygous deletion was pursued in the 15 samples and loss of heterozygosity was found in 11 tumours. Our data suggest that intragenic point mutations of GDNF or GFRalpha-1 are not a common aetiologic event in brain tumours. However, either deletion of GFRalpha-1 and/or nearby genes may contribute to the pathogenesis of these tumours.
Assuntos
Neoplasias Encefálicas/genética , Proteínas de Drosophila , Fatores de Crescimento Neural/genética , Proteínas do Tecido Nervoso/genética , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética , Análise Mutacional de DNA , DNA de Neoplasias/análise , DNA de Neoplasias/genética , Éxons , Deleção de Genes , Fator Neurotrófico Derivado de Linhagem de Célula Glial , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial , Humanos , Íntrons , Mutação , Fatores de Crescimento Neural/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Reação em Cadeia da Polimerase , Polimorfismo Genético , Proteínas Proto-Oncogênicas c-retRESUMO
The aetiology of sporadic medullary thyroid carcinoma is unknown. About 50% harbour a somatic mutation at codon 918 of RET (M918T). To investigate whether other RET sequence variants may be associated with or predispose to the development of sporadic medullary thyroid carcinoma, we analysed genomic DNA from the germline and corresponding tumour from 50 patients to identify RET sequence variants. In one patient, tumour DNA showed a novel somatic 12 bp in-frame deletion in exon 15. More interestingly, we found that the rare polymorphism at codon 836 (c.2439C > T; S836S) occurred at a significantly higher frequency than that in control individuals without sporadic medullary thyroid carcinoma (Fisher's exact test, P = 0.03). Further, among the nine evaluable cases with germline c.2439C/T, eight also had the somatic M918T mutation in MTC DNA which was more frequent than in patients with the more common c.2439C/C (89% vs 40%, respectively; Fisher's exact test, P = 0.01). These findings suggest that the rare sequence variant at codon 836 may somehow play a role in the genesis of sporadic medullary thyroid carcinoma.
Assuntos
Carcinoma Medular/genética , Proteínas de Drosophila , Mutação em Linhagem Germinativa , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética , Neoplasias da Glândula Tireoide/genética , Carcinoma Medular/etiologia , Códon , Variação Genética , Humanos , Neoplasia Endócrina Múltipla Tipo 2a/genética , Mutação Puntual , Proteínas Proto-Oncogênicas c-ret , Deleção de Sequência , Neoplasias da Glândula Tireoide/etiologiaRESUMO
PTEN is a novel tumour suppressor gene that encodes a dual-specificity phosphatase with homology to adhesion molecules tensin and auxillin. It recently has been suggested that PTEN dephosphorylates phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3, 4,5)P3], which mediates growth factor-induced activation of intracellular signalling, in particular through the serine-threonine kinase Akt, a known cell survival-promoting factor. PTEN has been mapped to 10q23.3, a region disrupted in several human tumours including haematological malignancies. We have analysed PTEN in a series of primary acute leukaemias and non-Hodgkin's lymphomas (NHLs) as well as in cell lines. We have also examined whether a correlation could be found between PTEN and Akt levels in these samples. We show here that the majority of cell lines studied carries PTEN abnormalities. At the structural level, we found mutations and hemizygous deletions in 40% of these cell lines, while a smaller number of primary haematological malignancies, in particular NHLs, carries PTEN mutations. Moreover, one-third of the cell lines had low PTEN transcript levels, and 60% of these samples had low or absent PTEN protein, which could not be attributed to gene silencing by hypermethylation. In addition, we found that PTEN and phosphorylated Akt levels are inversely correlated in the large majority of the examined samples. These findings suggest that PTEN plays a role in the pathogenesis of haematological malignancies and that it might be inactivated through a wider range of mechanisms than initially considered. The finding that PTEN levels inversely correlate with phosphorylated Akt supports the hypothesis that PTEN regulates PtdIns(3,4,5)P3and suggests a role for PTEN in apoptosis.