Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 19 de 19
Filter
1.
Transl Psychiatry ; 7(4): e1109, 2017 04 25.
Article in English | MEDLINE | ID: mdl-28440815

ABSTRACT

Several copy number variants have been associated with neuropsychiatric disorders and these variants have been shown to also influence cognitive abilities in carriers unaffected by psychiatric disorders. Previously, we associated the 15q11.2(BP1-BP2) deletion with specific learning disabilities and a larger corpus callosum. Here we investigate, in a much larger sample, the effect of the 15q11.2(BP1-BP2) deletion on cognitive, structural and functional correlates of dyslexia and dyscalculia. We report that the deletion confers greatest risk of the combined phenotype of dyslexia and dyscalculia. We also show that the deletion associates with a smaller left fusiform gyrus. Moreover, tailored functional magnetic resonance imaging experiments using phonological lexical decision and multiplication verification tasks demonstrate altered activation in the left fusiform and the left angular gyri in carriers. Thus, by using convergent evidence from neuropsychological testing, and structural and functional neuroimaging, we show that the 15q11.2(BP1-BP2) deletion affects cognitive, structural and functional correlates of both dyslexia and dyscalculia.


Subject(s)
Cognition/physiology , DNA Copy Number Variations/genetics , Dyscalculia/genetics , Dyslexia/genetics , Intellectual Disability/genetics , Adolescent , Adult , Aged , Chromosome Aberrations , Chromosome Deletion , Chromosomes, Human, Pair 15/genetics , Developmental Disabilities/genetics , Female , Functional Neuroimaging/methods , Functional Neuroimaging/standards , Heterozygote , Humans , Iceland/epidemiology , Magnetic Resonance Imaging/methods , Male , Middle Aged , Neuropsychological Tests/standards , Phenotype , Temporal Lobe/anatomy & histology , Temporal Lobe/diagnostic imaging , Young Adult
2.
Mol Psychiatry ; 22(6): 836-849, 2017 06.
Article in English | MEDLINE | ID: mdl-27240531

ABSTRACT

Copy number variants (CNVs) are major contributors to genomic imbalance disorders. Phenotyping of 137 unrelated deletion and reciprocal duplication carriers of the distal 16p11.2 220 kb BP2-BP3 interval showed that these rearrangements are associated with autism spectrum disorders and mirror phenotypes of obesity/underweight and macrocephaly/microcephaly. Such phenotypes were previously associated with rearrangements of the non-overlapping proximal 16p11.2 600 kb BP4-BP5 interval. These two CNV-prone regions at 16p11.2 are reciprocally engaged in complex chromatin looping, as successfully confirmed by 4C-seq, fluorescence in situ hybridization and Hi-C, as well as coordinated expression and regulation of encompassed genes. We observed that genes differentially expressed in 16p11.2 BP4-BP5 CNV carriers are concomitantly modified in their chromatin interactions, suggesting that disruption of chromatin interplays could participate in the observed phenotypes. We also identified cis- and trans-acting chromatin contacts to other genomic regions previously associated with analogous phenotypes. For example, we uncovered that individuals with reciprocal rearrangements of the trans-contacted 2p15 locus similarly display mirror phenotypes on head circumference and weight. Our results indicate that chromosomal contacts' maps could uncover functionally and clinically related genes.


Subject(s)
Autistic Disorder/genetics , Chromosome Mapping/methods , Chromosomes, Human, Pair 16/physiology , Obesity/genetics , Adolescent , Adult , Aged , Autism Spectrum Disorder/genetics , Body Mass Index , Child , Child, Preschool , Chromatin/metabolism , Chromatin/physiology , Chromosome Deletion , Chromosome Duplication , Chromosomes, Human, Pair 16/genetics , DNA Copy Number Variations/genetics , Female , Humans , In Situ Hybridization, Fluorescence , Infant , Intellectual Disability/genetics , Male , Megalencephaly/genetics , Microcephaly/genetics , Middle Aged , Phenotype
3.
Mol Psychiatry ; 21(5): 594-600, 2016 May.
Article in English | MEDLINE | ID: mdl-26952864

ABSTRACT

Using Icelandic whole-genome sequence data and an imputation approach we searched for rare sequence variants in CHRNA4 and tested them for association with nicotine dependence. We show that carriers of a rare missense variant (allele frequency=0.24%) within CHRNA4, encoding an R336C substitution, have greater risk of nicotine addiction than non-carriers as assessed by the Fagerstrom Test for Nicotine Dependence (P=1.2 × 10(-4)). The variant also confers risk of several serious smoking-related diseases previously shown to be associated with the D398N substitution in CHRNA5. We observed odds ratios (ORs) of 1.7-2.3 for lung cancer (LC; P=4.0 × 10(-4)), chronic obstructive pulmonary disease (COPD; P=9.3 × 10(-4)), peripheral artery disease (PAD; P=0.090) and abdominal aortic aneurysms (AAAs; P=0.12), and the variant associates strongly with the early-onset forms of LC (OR=4.49, P=2.2 × 10(-4)), COPD (OR=3.22, P=2.9 × 10(-4)), PAD (OR=3.47, P=9.2 × 10(-3)) and AAA (OR=6.44, P=6.3 × 10(-3)). Joint analysis of the four smoking-related diseases reveals significant association (P=6.8 × 10(-5)), particularly for early-onset cases (P=2.1 × 10(-7)). Our results are in agreement with functional studies showing that the human α4ß2 isoform of the channel containing R336C has less sensitivity for its agonists than the wild-type form following nicotine incubation.


Subject(s)
Genetic Predisposition to Disease , Mutation, Missense , Receptors, Nicotinic/genetics , Smoking/genetics , Tobacco Use Disorder/complications , Tobacco Use Disorder/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Aortic Aneurysm, Abdominal/etiology , Aortic Aneurysm, Abdominal/genetics , Female , Genetic Association Studies , Humans , Iceland , Lung Neoplasms/etiology , Lung Neoplasms/genetics , Male , Middle Aged , Peripheral Arterial Disease/etiology , Peripheral Arterial Disease/genetics , Pulmonary Disease, Chronic Obstructive/etiology , Pulmonary Disease, Chronic Obstructive/genetics , White People/genetics , Young Adult
5.
Transl Psychiatry ; 3: e308, 2013 Oct 01.
Article in English | MEDLINE | ID: mdl-24084939

ABSTRACT

Smoking influences body weight such that smokers weigh less than non-smokers and smoking cessation often leads to weight increase. The relationship between body weight and smoking is partly explained by the effect of nicotine on appetite and metabolism. However, the brain reward system is involved in the control of the intake of both food and tobacco. We evaluated the effect of single-nucleotide polymorphisms (SNPs) affecting body mass index (BMI) on smoking behavior, and tested the 32 SNPs identified in a meta-analysis for association with two smoking phenotypes, smoking initiation (SI) and the number of cigarettes smoked per day (CPD) in an Icelandic sample (N=34,216 smokers). Combined according to their effect on BMI, the SNPs correlate with both SI (r=0.019, P=0.00054) and CPD (r=0.032, P=8.0 × 10(-7)). These findings replicate in a second large data set (N=127,274, thereof 76,242 smokers) for both SI (P=1.2 × 10(-5)) and CPD (P=9.3 × 10(-5)). Notably, the variant most strongly associated with BMI (rs1558902-A in FTO) did not associate with smoking behavior. The association with smoking behavior is not due to the effect of the SNPs on BMI. Our results strongly point to a common biological basis of the regulation of our appetite for tobacco and food, and thus the vulnerability to nicotine addiction and obesity.


Subject(s)
Obesity/genetics , Smoking/genetics , Tobacco Use Disorder/genetics , Age of Onset , Behavior, Addictive/genetics , Body Mass Index , Humans , Iceland/epidemiology , Polymorphism, Single Nucleotide , Smoking/epidemiology
6.
Mol Psychiatry ; 17(11): 1116-29, 2012 Nov.
Article in English | MEDLINE | ID: mdl-21876539

ABSTRACT

Coffee consumption is a model for addictive behavior. We performed a meta-analysis of genome-wide association studies (GWASs) on coffee intake from 8 Caucasian cohorts (N=18 176) and sought replication of our top findings in a further 7929 individuals. We also performed a gene expression analysis treating different cell lines with caffeine. Genome-wide significant association was observed for two single-nucleotide polymorphisms (SNPs) in the 15q24 region. The two SNPs rs2470893 and rs2472297 (P-values=1.6 × 10(-11) and 2.7 × 10(-11)), which were also in strong linkage disequilibrium (r(2)=0.7) with each other, lie in the 23-kb long commonly shared 5' flanking region between CYP1A1 and CYP1A2 genes. CYP1A1 was found to be downregulated in lymphoblastoid cell lines treated with caffeine. CYP1A1 is known to metabolize polycyclic aromatic hydrocarbons, which are important constituents of coffee, whereas CYP1A2 is involved in the primary metabolism of caffeine. Significant evidence of association was also detected at rs382140 (P-value=3.9 × 10(-09)) near NRCAM-a gene implicated in vulnerability to addiction, and at another independent hit rs6495122 (P-value=7.1 × 10(-09))-an SNP associated with blood pressure-in the 15q24 region near the gene ULK3, in the meta-analysis of discovery and replication cohorts. Our results from GWASs and expression analysis also strongly implicate CAB39L in coffee drinking. Pathway analysis of differentially expressed genes revealed significantly enriched ubiquitin proteasome (P-value=2.2 × 10(-05)) and Parkinson's disease pathways (P-value=3.6 × 10(-05)).


Subject(s)
Cell Adhesion Molecules/genetics , Coffee/genetics , Cytochrome P-450 CYP1A1/genetics , Cytochrome P-450 CYP1A2/genetics , Drinking/genetics , Genome-Wide Association Study/methods , Antigens, Neoplasm/genetics , Apoptosis Regulatory Proteins/genetics , Caffeine/pharmacology , Cell Line , Female , Gene Expression/drug effects , Gene Expression Profiling/methods , Genetic Predisposition to Disease/genetics , Humans , Male , Parkinson Disease/genetics , Polymorphism, Single Nucleotide , Protein Serine-Threonine Kinases/genetics , White People/genetics
7.
Mol Psychiatry ; 16(1): 59-66, 2011 Jan.
Article in English | MEDLINE | ID: mdl-20048749

ABSTRACT

A trio of genome-wide association studies recently reported sequence variants at three loci to be significantly associated with schizophrenia. No sequence polymorphism had been unequivocally (P<5 × 10(-8)) associated with schizophrenia earlier. However, one variant, rs1344706[T], had come very close. This polymorphism, located in an intron of ZNF804A, was reported to associate with schizophrenia with a P-value of 1.6 × 10(-7), and with psychosis (schizophrenia plus bipolar disorder) with a P-value of 1.0 × 10(-8). In this study, using 5164 schizophrenia cases and 20,709 controls, we replicated the association with schizophrenia (odds ratio OR = 1.08, P = 0.0029) and, by adding bipolar disorder patients, we also confirmed the association with psychosis (added N = 609, OR = 1.09, P = 0.00065). Furthermore, as it has been proposed that variants such as rs1344706[T]-common and with low relative risk-may also serve to identify regions harboring less common, higher-risk susceptibility alleles, we searched ZNF804A for large copy number variants (CNVs) in 4235 psychosis patients, 1173 patients with other psychiatric disorders and 39,481 controls. We identified two CNVs including at least part of ZNF804A in psychosis patients and no ZNF804A CNVs in controls (P = 0.013 for association with psychosis). In addition, we found a ZNF804A CNV in an anxiety patient (P = 0.0016 for association with the larger set of psychiatric disorders).


Subject(s)
Anxiety Disorders/genetics , Bipolar Disorder/genetics , DNA Copy Number Variations/genetics , Kruppel-Like Transcription Factors/genetics , Schizophrenia/genetics , Case-Control Studies , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Reference Values
8.
J Med Genet ; 45(5): 284-9, 2008 May.
Article in English | MEDLINE | ID: mdl-18178632

ABSTRACT

BACKGROUND: Germline CDKN2A mutations have been observed in 20-40% of high risk, melanoma prone families; however, little is known about their prevalence in population based series of melanoma cases and controls. METHODS: We resequenced the CDKN2A gene, including the p14ARF variant and promoter regions, in approximately 703 registry ascertained melanoma cases and 691 population based controls from Iceland, a country in which the incidence of melanoma has increased rapidly. RESULTS: We identified a novel germline variant, G89D, that was strongly associated with increased melanoma risk and appeared to be an Icelandic founder mutation. The G89D variant was present in about 2% of Icelandic invasive cutaneous malignant melanoma cases. Relatives of affected G89D carriers were at significantly increased risk of melanoma, head and neck cancers, and pancreatic carcinoma compared to relatives of other melanoma patients. Nineteen other germline variants were identified, but none conferred an unequivocal risk of melanoma. CONCLUSIONS: This population based study of Icelandic melanoma cases and controls showed a frequency of disease related CDKN2A mutant alleles ranging from 0.7% to 1.0%, thus expanding our knowledge about the frequency of CDKN2A mutations in different populations. In contrast to North America and Australia where a broad spectrum of mutations was observed at a similar frequency, in Iceland, functional CDKN2A mutations consist of only one or two different variants. Additional genetic and/or environmental factors are likely critical for explaining the high incidence rates for melanoma in Iceland. This study adds to the geographic regions for which population based estimates of CDKN2A mutation frequencies are available.


Subject(s)
Genes, p16 , Germ-Line Mutation , Melanoma/epidemiology , Melanoma/genetics , Alleles , Australia , Case-Control Studies , Gene Frequency , Genotype , Humans , Iceland/epidemiology , North America , Population Groups , Risk Factors
9.
Am J Hum Genet ; 76(3): 505-9, 2005 Mar.
Article in English | MEDLINE | ID: mdl-15640973

ABSTRACT

Cardiovascular diseases, including myocardial infarction (MI) and stroke, most often occur on the background of atherosclerosis, a condition attributed to the interactions between multiple genetic and environmental risk factors. We recently reported a linkage and association study of MI and stroke that yielded a genetic variant, HapA, in the gene encoding 5-lipoxygenase-activating protein (ALOX5AP), that associates with both diseases in Iceland. We also described another ALOX5AP variant, HapB, that associates with MI in England. To further assess the contribution of the ALOX5AP variants to cardiovascular diseases in a population outside Iceland, we genotyped seven single-nucleotide polymorphisms that define both HapA and HapB from 450 patients with ischemic stroke and 710 controls from Aberdeenshire, Scotland. The Icelandic at-risk haplotype, HapA, had significantly greater frequency in Scottish patients than in controls. The carrier frequency in patients and controls was 33.4% and 26.4%, respectively, which resulted in a relative risk of 1.36, under the assumption of a multiplicative model (P=.007). We did not detect association between HapB and ischemic stroke in the Scottish cohort. However, we observed that HapB was overrepresented in male patients. This replication of haplotype association with stroke in a population outside Iceland further supports a role for ALOX5AP in cardiovascular diseases.


Subject(s)
Carrier Proteins/genetics , Membrane Proteins/genetics , Stroke/genetics , 5-Lipoxygenase-Activating Proteins , Aged , Case-Control Studies , Female , Gene Frequency , Genetic Variation , Genotype , Haplotypes , Humans , Iceland , Male , Middle Aged , Polymorphism, Single Nucleotide , Risk Factors , Scotland
10.
EMBO J ; 20(3): 350-61, 2001 Feb 01.
Article in English | MEDLINE | ID: mdl-11157742

ABSTRACT

Here we describe hemopoietic chimeras serving as a mouse model for NUP98-HOXA9-induced leukemia, which reproduced several of the phenotypes observed in human disease. Mice transplanted with bone marrow cells expressing NUP98-HOXA9 through retroviral transduction acquire a myeloproliferative disease (MPD) and eventually succumb to acute myeloid leukemia (AML). The NUP98 portion of the fusion protein was shown to be responsible for transforming a clinically silent pre-leukemic phase observed for Hoxa9 into a chronic, stem cell-derived MPD. The co-expression of NUP98-HOXA9 and Meis1 accelerated the transformation of MPD to AML, identifying a genetic interaction previously observed for Hoxa9 and Meis1. Our findings demonstrate the presence of overlapping yet distinct molecular mechanisms for MPD versus AML, illustrating the complexity of leukemic transformation.


Subject(s)
Hematopoietic Stem Cells/metabolism , Leukemia, Experimental/etiology , Nuclear Pore Complex Proteins , Oncogene Proteins, Fusion/genetics , Animals , Bone Marrow Transplantation , Cell Transformation, Neoplastic/genetics , Chimera , Gene Expression , Homeodomain Proteins/genetics , Humans , Leukemia, Experimental/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/etiology , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Leukemia, Myeloid, Acute/etiology , Leukemia, Myeloid, Acute/genetics , Mice , Mice, Inbred C3H , Mice, Inbred C57BL , Myeloid Ecotropic Viral Integration Site 1 Protein , Myeloproliferative Disorders/etiology , Myeloproliferative Disorders/genetics , Neoplasm Proteins/genetics , Retroviridae/genetics , Transduction, Genetic
11.
Mol Cell Biol ; 21(1): 224-34, 2001 Jan.
Article in English | MEDLINE | ID: mdl-11113197

ABSTRACT

Complex genetic and biochemical interactions between HOX proteins and members of the TALE (i.e., PBX and MEIS) family have been identified in embryonic development, and some of these interactions also appear to be important for leukemic transformation. We have previously shown that HOXA9 collaborates with MEIS1 in the induction of acute myeloid leukemia (AML). In this report, we demonstrate that HOXB3, which is highly divergent from HOXA9, also genetically interacts with MEIS1, but not with PBX1, in generating AML. In addition, we show that the HOXA9 and HOXB3 genes play key roles in establishing all the main characteristics of the leukemias, while MEIS1 functions only to accelerate the onset of the leukemic transformation. Contrasting the reported functional similarities between PREP1 and MEIS1, such as PBX nuclear retention, we also show that PREP1 overexpression is incapable of accelerating the HOXA9-induced AML, suggesting that MEIS1 function in transformation must entail more than PBX nuclear localization. Collectively, these data demonstrate that MEIS1 is a common leukemic collaborator with two structurally and functionally divergent HOX genes and that, in this collaboration, the HOX gene defines the identity of the leukemia.


Subject(s)
Cell Transformation, Neoplastic , Homeodomain Proteins/metabolism , Leukemia, Myeloid/pathology , Neoplasm Proteins/metabolism , Xenopus Proteins , Acute Disease , Animals , Bone Marrow Cells/metabolism , Bone Marrow Cells/virology , Bone Marrow Transplantation , Cells, Cultured , Chimera/genetics , Chimera/metabolism , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Disease Progression , Histocytochemistry , Homeodomain Proteins/genetics , Leukemia, Myeloid/genetics , Leukemia, Myeloid/metabolism , Mice , Mice, Inbred Strains , Myeloid Ecotropic Viral Integration Site 1 Protein , Neoplasm Proteins/genetics , Phenotype , Pre-B-Cell Leukemia Transcription Factor 1 , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolism , Transduction, Genetic
12.
Blood ; 94(8): 2605-12, 1999 Oct 15.
Article in English | MEDLINE | ID: mdl-10515864

ABSTRACT

After bone marrow transplantation (BMT), there is a rapid regeneration to normal pretransplantation levels in the number of hematopoietic progenitors and mature end cells, whereas hematopoietic stem cell (HSC) numbers recover to only 5% to 10% of normal levels. This suggests that HSC are significantly restricted in their self-renewal behavior and hence in their ability to repopulate the host stem cell compartment. Previously, we have reported that HSC engineered to overexpress the homeobox transcription factor HOXB4 have a large repopulation advantage over untransduced cells as assessed at 4 months in a murine transplantation model (Sauvageau et al, Genes Dev 9:1753, 1995). This phenomenon has now been examined in detail for periods extending to 12 months in cohorts of mice transplanted with various numbers of HOXB4-transduced HSC. In all mice analyzed, HOXB4-transduced HSC were capable of fully reconstituting the HSC compartment, resulting, on average, in some 14-fold greater numbers of HSC than observed when transplanting control, non-HOXB4-transduced bone marrow cells. These data indicate that HOXB4 is a limiting factor in the regeneration of HSC to normal levels after BMT. Furthermore, we show that HOXB4-transduced HSC did not expand above levels normally observed in unmanipulated mice, indicating that its overexpression does not override the regulatory mechanisms that maintain the HSC pool size within normal limits.


Subject(s)
Hematopoietic Stem Cells/cytology , Homeodomain Proteins/physiology , Transcription Factors/physiology , Animals , Bone Marrow Cells/cytology , Bone Marrow Transplantation , Cell Count , Cell Division , Cells, Cultured/transplantation , Colony-Forming Units Assay , Female , Gene Expression Regulation , Genetic Vectors/genetics , Graft Survival , Hematopoietic Stem Cell Transplantation , Homeodomain Proteins/genetics , Male , Mice , Mice, Inbred C3H , Mice, Inbred C57BL , Radiation Chimera , Recombinant Fusion Proteins/physiology , Retroviridae/genetics , Transcription Factors/genetics
13.
Genes Dev ; 13(20): 2691-703, 1999 Oct 15.
Article in English | MEDLINE | ID: mdl-10541555

ABSTRACT

The murine Polycomb-Group (PcG) proteins Eed and Bmi1 govern axial patterning during embryonic development by segment-specific repression of Hox gene expression. The two proteins engage in distinct multimeric complexes that are thought to use a common molecular mechanism to render the regulatory regions of Hox and other downstream target genes inaccessible to transcriptional activators. Beyond axial patterning, Bmi1 is also involved in hemopoiesis because a loss-of-function allele causes a profound decrease in bone marrow progenitor cells. Here, evidence is presented that is consistent with an antagonistic function of eed and Bmi1 in hemopoietic cell proliferation. Heterozygosity for an eed null allele causes marked myelo- and lymphoproliferative defects, indicating that eed is involved in the negative regulation of the pool size of lymphoid and myeloid progenitor cells. This antiproliferative function of eed does not appear to be mediated by Hox genes or the tumor suppressor locus p16(INK4a)/p19(ARF) because expression of these genes was not altered in eed mutants. Intercross experiments between eed and Bmi1 mutant mice revealed that Bmi1 is epistatic to eed in the control of primitive bone marrow cell proliferation. However, the genetic interaction between the two genes is cell-type specific as the presence of one or two mutant alleles of eed trans-complements the Bmi1-deficiency in pre-B bone marrow cells. These studies thus suggest that hemopoietic cell proliferation is regulated by the relative contribution of repressive (Eed-containing) and enhancing (Bmi1-containing) PcG gene complexes.


Subject(s)
Hematopoiesis/genetics , Nuclear Proteins/genetics , Proto-Oncogene Proteins/genetics , Repressor Proteins/genetics , Aging/genetics , Aging/pathology , Animals , Cell Division/genetics , Colony-Forming Units Assay , Female , Gene Expression Regulation, Developmental , Genes, Homeobox , Genes, Regulator , Genes, p16 , Hematopoietic Stem Cells/cytology , Male , Mice , Mice, Inbred C3H , Mice, Knockout , Polycomb Repressive Complex 1 , Polycomb Repressive Complex 2 , Polycomb-Group Proteins
14.
Mol Cell Biol ; 19(9): 6355-66, 1999 Sep.
Article in English | MEDLINE | ID: mdl-10454582

ABSTRACT

A recurrent translocation between chromosome 1 (Pbx1) and 19 (E2A) leading to the expression of the E2A-Pbx1 fusion oncoprotein occurs in approximately 5 to 10% of acute leukemias in humans. It has been proposed that some of the oncogenic potential of E2A-Pbx1 could be mediated through heterocomplex formation with Hox proteins, which are also involved in human and mouse leukemias. To directly test this possibility, mouse bone marrow cells were engineered by retroviral gene transfer to overexpress E2A-Pbx1a together with Hoxa9. The results obtained demonstrated a strong synergistic interaction between E2A-Pbx1a and Hoxa9 in inducing growth factor-independent proliferation of transduced bone marrow cells in vitro and leukemic growth in vivo in only 39 +/- 2 days. The leukemic blasts which coexpress E2A-Pbx1a and Hoxa9 showed little differentiation and produced cytokines such as interleukin-3, granulocyte colony-stimulating factor, and Steel. Together, these studies demonstrate that the Hoxa9 and E2A-Pbx1a gene products collaborate to produce a highly aggressive acute leukemic disease.


Subject(s)
Homeodomain Proteins/physiology , Oncogene Proteins, Fusion/physiology , Animals , Bone Marrow Cells/pathology , Cell Division , Cell Transformation, Neoplastic , Gene Expression , Gene Transfer Techniques , Homeodomain Proteins/genetics , Humans , Leukemia, Experimental/genetics , Mice , Neoplasm Transplantation , Oncogene Proteins, Fusion/genetics , Translocation, Genetic
15.
EMBO J ; 17(13): 3714-25, 1998 Jul 01.
Article in English | MEDLINE | ID: mdl-9649441

ABSTRACT

Hoxa9, Meis1 and Pbx1 encode homeodomaincontaining proteins implicated in leukemic transformation in both mice and humans. Hoxa9, Meis1 and Pbx1 proteins have been shown to physically interact with each other, as Hoxa9 cooperatively binds consensus DNA sequences with Meis1 and with Pbx1, while Meis1 and Pbx1 form heterodimers in both the presence and absence of DNA. In this study, we sought to determine if Hoxa9 could transform hemopoietic cells in collaboration with either Pbx1 or Meis1. Primary bone marrow cells, retrovirally engineered to overexpress Hoxa9 and Meis1a simultaneously, induced growth factor-dependent oligoclonal acute myeloid leukemia in <3 months when transplanted into syngenic mice. In contrast, overexpression of Hoxa9, Meis1a or Pbx1b alone, or the combination of Hoxa9 and Pbx1b failed to transform these cells acutely within 6 months post-transplantation. Similar results were obtained when FDC-P1 cells, engineered to overexpress these genes, were transplanted to syngenic recipients. Thus, these studies demonstrate a selective collaboration between a member of the Hox family and one of its DNA-binding partners in transformation of hemopoietic cells.


Subject(s)
Bone Marrow Cells/metabolism , Cell Transformation, Neoplastic , DNA-Binding Proteins/metabolism , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , Proto-Oncogene Proteins/metabolism , Animals , Cell Line , Cell Transplantation , Cells, Cultured , DNA-Binding Proteins/genetics , Female , Genetic Vectors , Humans , Leukemia, Myeloid/etiology , Male , Mice , Mice, Inbred C3H , Mice, Inbred C57BL , Myeloid Ecotropic Viral Integration Site 1 Protein , Pre-B-Cell Leukemia Transcription Factor 1 , Proto-Oncogene Proteins/genetics , Research Design , Retroviridae
16.
Mol Cell Biol ; 17(1): 495-505, 1997 Jan.
Article in English | MEDLINE | ID: mdl-8972230

ABSTRACT

Multiple members of the A, B, and C clusters of Hox genes are expressed in hematopoietic cells. Several of these Hox genes have been found to display distinctive expression patterns, with genes located at the 3' side of the clusters being expressed at their highest levels in the most primitive subpopulation of human CD34+ bone marrow cells and genes located at the 5' end having a broader range of expression, with downregulation at later stages of hematopoietic differentiation. To explore if these patterns reflect different functional activities, we have retrovirally engineered the overexpression of a 5'-located gene, HOXA10, in murine bone marrow cells and demonstrate effects strikingly different from those induced by overexpression of a 3'-located gene, HOXB4. In contrast to HOXB4, which causes selective expansion of primitive hematopoietic cells without altering their differentiation, overexpression of HOXA10 profoundly perturbed myeloid and B-lymphoid differentiation. The bone marrow of mice reconstituted with HOXA10-transduced bone marrow cells contained in high frequency a unique progenitor cell with megakaryocytic colony-forming ability and was virtually devoid of unilineage macrophage and pre-B-lymphoid progenitor cells derived from the transduced cells. Moreover, and again in contrast to HOXB4, a significant proportion of HOXA10 mice developed a transplantable acute myeloid leukemia with a latency of 19 to 50 weeks. These results thus add to recognition of Hox genes as important regulators of hematopoiesis and provide important new evidence of Hox gene-specific functions that may correlate with their normal expression pattern.


Subject(s)
DNA-Binding Proteins/genetics , Hematopoiesis/genetics , Hematopoietic Stem Cells/metabolism , Homeodomain Proteins , Leukemia, Myeloid/genetics , Acute Disease , Animals , B-Lymphocytes , Bone Marrow Cells , Bone Marrow Transplantation , Cell Differentiation , Female , Gene Transfer Techniques , Genes, Homeobox/genetics , Homeobox A10 Proteins , Humans , Lymphoid Tissue/cytology , Male , Mice , Mice, Inbred C3H , Mice, Inbred C57BL , RNA, Messenger/analysis , Retroviridae/genetics
17.
Immunity ; 6(1): 13-22, 1997 Jan.
Article in English | MEDLINE | ID: mdl-9052833

ABSTRACT

HOXB3 mRNA levels are high in the earliest CD34+ lineage- bone marrow cells and low to undetectable in later CD34+/CD34- cells. To gain some insight into the role this gene may play in hematopoiesis, HOXB3 was overexpressed in murine bone marrow cells using retroviral gene transfer. Thymi of HOXB3 marrow recipients were reduced in size compared with control transplant recipients, with a 24-fold decrease in the absolute number of CD4+ CD8+ cells and a 3-fold increase in the number of CD4- CD8- thymocytes that contained a high proportion of gammadelta TCR+ cells. B cell differentiation was also perturbed in these mice, as indicated by the virtual absence of transduced IL-7-responsive pre-B clonogenic progenitors. Recipients of HOXB3-transduced cells also had elevated numbers of mature granulocyte macrophage colony-forming cells in their bone marrow and spleen. Together these results suggest roles for HOXB3 in proliferation and differentiation processes of both early myeloid and lymphoid developmental pathways.


Subject(s)
B-Lymphocytes/cytology , Genes, Homeobox , Granulocytes/cytology , Hematopoiesis , Homeodomain Proteins/genetics , Myeloproliferative Disorders/genetics , T-Lymphocytes/cytology , Xenopus Proteins , Animals , Antigens, CD34/analysis , Bone Marrow Cells , Female , Male , Mice , Mice, Inbred C3H , Mice, Inbred C57BL , Spleen/cytology , Transduction, Genetic
18.
Hematol Oncol Clin North Am ; 11(6): 1221-37, 1997 Dec.
Article in English | MEDLINE | ID: mdl-9443054

ABSTRACT

Hox genes, first recognized for their role in embryonic development, may also play lineage-specific functions in a variety of somatic tissues including the hematopoietic system. Expression of these transcription factors has been demonstrated both in normal and leukemic human and hematopoietic cells, suggesting functional roles in hematopoietic cell growth and differentiation. Several recent studies have shown that Hox proteins are involved in controlling proliferation of primitive bone marrow cells and also in altering differentiation of myeloid as well as lymphoid progenitors, alterations that also can contribute to leukemic transformation. Hox genes, together with their upstream regulators and downstream target genes, may play key roles in fundamental processes controlling hematopoietic stem cell properties.


Subject(s)
Genes, Homeobox/physiology , Hematopoiesis , Leukemia , Animals , Homeodomain Proteins/genetics , Homeodomain Proteins/physiology , Homeostasis , Humans
19.
Genes Dev ; 9(14): 1753-65, 1995 Jul 15.
Article in English | MEDLINE | ID: mdl-7622039

ABSTRACT

Hox genes were first recognized for their role in embryonic development and may also play important lineage-specific functions in a variety of somatic tissues including the hematopoietic system. We have recently shown that certain members of the Hox A and B clusters, such as HOXB3 and HOXB4, are preferentially expressed in subpopulations of human bone marrow that are highly enriched for the most primitive hematopoietic cell types. To assess the role these genes may play in regulating the proliferation and/or differentiation of such cells, we engineered the overexpression of HOXB4 in murine bone marrow cells by retroviral gene transfer and analyzed subsequent effects on the behavior of various hematopoietic stem and progenitor cell populations both in vitro and in vivo. Serial transplantation studies revealed a greatly enhanced ability of HOXB4-transduced bone marrow cells to regenerate the most primitive hematopoietic stem cell compartment resulting in 50-fold higher numbers of transplantable totipotent hematopoietic stem cells in primary and secondary recipients, compared with serially passaged neo-infected control cells. This heightened expansion in vivo of HOXB4-transduced hematopoietic stem cells was not accompanied by identifiable anomalies in the peripheral blood of these mice. Enhanced proliferation in vitro of day-12 CFU-S and clonogenic progenitors was also documented. These results indicate HOXB4 to be an important regulator of very early but not late hematopoietic cell proliferation and suggest a new approach to the controlled amplification of genetically modified hematopoietic stem cell populations.


Subject(s)
Genes, Homeobox , Hematopoietic Stem Cells/metabolism , Animals , Bone Marrow Transplantation , Cell Line , Colony-Forming Units Assay , Female , Gene Expression , Hematopoiesis/genetics , Humans , In Vitro Techniques , Male , Mice , Mice, Inbred C3H , Mice, Inbred C57BL , Retroviridae/genetics , Transduction, Genetic
SELECTION OF CITATIONS
SEARCH DETAIL
...