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1.
Can J Physiol Pharmacol ; 102(1): 1-13, 2024 Jan 01.
Article in English | MEDLINE | ID: mdl-37903419

ABSTRACT

Cardiovascular diseases remain a leading cause of hospitalization affecting approximately 38 million people worldwide. While pharmacological and revascularization techniques can improve the patient's survival and quality of life, they cannot help reversing myocardial infarction injury and heart failure. Direct reprogramming of somatic cells to cardiomyocyte and cardiac progenitor cells offers a new approach to cellular reprogramming and paves the way for translational regenerative medicine. Direct reprogramming can bypass the pluripotent stage with the potential advantage of non-immunogenic cell products, reduced carcinogenic risk, and no requirement for embryonic tissue. The process of directly reprogramming cardiac cells was first achieved through the overexpression of transcription factors such as GATA4, MEF2C, and TBX5. However, over the past decade, significant work has been focused on enhancing direct reprogramming using a mixture of transcription factors, microRNAs, and small molecules to achieve cardiac cell fate. This review discusses the evolution of direct reprogramming, recent progress in achieving efficient cardiac cell fate conversion, and describes the reprogramming mechanisms at a molecular level. We also explore various viral and non-viral delivery methods currently being used to aid in the delivery of reprogramming factors to improve efficiency. However, further studies will be needed to overcome molecular and epigenetic barriers to successfully achieve translational cardiac regenerative therapeutics.


Subject(s)
Cellular Reprogramming Techniques , Quality of Life , Humans , Cellular Reprogramming Techniques/methods , Myocytes, Cardiac , Cellular Reprogramming , Transcription Factors/genetics , Regenerative Medicine/methods , Fibroblasts
2.
Aging Cell ; 22(10): e13964, 2023 10.
Article in English | MEDLINE | ID: mdl-37594403

ABSTRACT

Bloom syndrome (BSyn) is an autosomal recessive disorder caused by variants in the BLM gene, which is involved in genome stability. Patients with BSyn present with poor growth, sun sensitivity, mild immunodeficiency, diabetes, and increased risk of cancer, most commonly leukemias. Interestingly, patients with BSyn do not have other signs of premature aging such as early, progressive hair loss and cataracts. We set out to determine epigenetic age in BSyn, which can be a better predictor of health and disease over chronological age. Our results show for the first time that patients with BSyn have evidence of accelerated epigenetic aging across several measures in blood lymphocytes, as compared to carriers. Additionally, homozygous Blm mice exhibit accelerated methylation age in multiple tissues, including brain, blood, kidney, heart, and skin, according to the brain methylation clock. Overall, we find that Bloom syndrome is associated with accelerated epigenetic aging effects in multiple tissues and more generally a strong effect on CpG methylation levels.


Subject(s)
Aging, Premature , Bloom Syndrome , Humans , Animals , Mice , Bloom Syndrome/genetics , Bloom Syndrome/diagnosis , Epigenesis, Genetic , Aging/genetics , Aging, Premature/genetics , Methylation , DNA Methylation/genetics
3.
Pediatr Hematol Oncol ; 40(8): 800-806, 2023.
Article in English | MEDLINE | ID: mdl-37334681

ABSTRACT

Crouzon Syndrome is a genetic craniosynostosis disorder associated with a high risk of ophthalmologic sequelae secondary to structural causes. However, ophthalmologic disorders due to intrinsic nerve aberrations in Crouzon Syndrome have not been described. Optic pathway gliomas (OPGs) are low grade gliomas that are intrinsic to the visual pathway, frequently associated with Neurofibromatosis type 1 (NF-1). OPGs involving both optic nerves without affecting the optic chiasm are rarely seen outside of NF-1. We report an unusual case of bilateral optic nerve glioma without chiasmatic involvement in a 17-month-old male patient with Crouzon Syndrome without any clinical or genetic findings of NF-1. This case suggests that close ophthalmologic follow up and orbital MRIs may benefit patients with Crouzon Syndrome.


Subject(s)
Craniofacial Dysostosis , Neurofibromatosis 1 , Optic Nerve Glioma , Optic Nerve Neoplasms , Humans , Male , Infant , Optic Nerve Glioma/complications , Visual Pathways , Optic Nerve Neoplasms/complications , Craniofacial Dysostosis/complications
4.
PLoS One ; 18(3): e0281949, 2023.
Article in English | MEDLINE | ID: mdl-36947496

ABSTRACT

BACKGROUND: While there are many epidemiologic studies of Asian immigrants to the West and risk of inflammatory bowel disease (IBD), the phenotype and lifestyle of Asian patients, particularly children, with IBD are not well described. In this study, we describe lifestyle practices, such as dietary pattern, as well as disease phenotype in Asian American children with IBD. METHODS: We reviewed the records of children with IBD, ages 0 to 21 years old, and race identified as Asian, Indian, or Pacific Islander. Patients who received outpatient IBD care at our center between January 2013 and January 2020 were included. We excluded patients who were international second opinions, who did not have a definitive diagnosis of IBD, and in whom a diagnosis of IBD was made after 18 years of age. A survey, including a food frequency questionnaire adapted from NHANES DSQ with modifications to include culturally appropriate food elements, was designed and conducted within this cohort to assess for dietary patterns. RESULTS: Asian patients in our cohort have similar phenotypes as non-Asians with few distinctive differences. There was a Crohn's disease and male predominance similar with non-Asians. However, there was a high rate of proctitis in ulcerative colitis in Asian patients. Asian patients reported a typical dietary pattern that reflects a Westernized pattern rather than a traditional pattern. Despite a similar dietary pattern, there was a high rate of 25-OH Vitamin D deficiency (44%) and insufficiency (40%). CONCLUSIONS: This single center study showed that the phenotype of Asian children with IBD in the U.S. is similar with that of non-Asian with a few distinct differences. The Asian children in our cohort reported following a Westernized dietary pattern and lifestyle. However, there was a high rate of Vitamin D deficiency surrounding diagnosis, suggesting a need for vigilant monitoring.


Subject(s)
Colitis, Ulcerative , Inflammatory Bowel Diseases , Vitamin D Deficiency , Female , Humans , Male , Asian , Inflammatory Bowel Diseases/epidemiology , Life Style , Nutrition Surveys , Infant, Newborn , Infant , Child, Preschool , Child , Adolescent , Young Adult , United States
5.
Trends Pharmacol Sci ; 44(6): 321-323, 2023 06.
Article in English | MEDLINE | ID: mdl-36997381

ABSTRACT

Letters of recommendation are ubiquitous in the research enterprise. Requesting, writing, and reviewing letters of recommendation are all fraught with bias, especially for individuals from groups historically excluded from research environments. We detail how letter reviewers, requesters, and writers can make letters of recommendation a more equitable tool to evaluate scientists.


Subject(s)
Internship and Residency , Humans , Writing
6.
Blood Adv ; 6(21): 5732-5736, 2022 11 08.
Article in English | MEDLINE | ID: mdl-35914227

ABSTRACT

Autologous stem cell transplant with gene therapy (ASCT-GT) provides curative therapy while reducing pretransplant immune-suppressive conditioning and eliminating posttransplant immune suppression. Clonal hematopoiesis of indeterminate potential (CHIP)-associated mutations increase and telomere lengths (TLs) shorten with natural aging and DNA damaging processes. It is possible that, if CHIP is present before ASCT-GT or mutagenesis occurs after busulfan exposure, the hematopoietic stem cells carrying these somatic variants may survive the conditioning chemotherapy and have a selective reconstitution advantage, increasing the risk of hematologic malignancy and overall mortality. Seventy-four peripheral blood samples (ranging from baseline to 120 months after ASCT-GT) from 10 pediatric participants who underwent ASCT-GT for adenosine deaminase-deficient severe combined immune deficiency (ADA-SCID) after reduced-intensity conditioning with busulfan and 16 healthy controls were analyzed for TL and CHIP. One participant had a significant decrease in TL. There were no CHIP-associated mutations identified by the next-generation sequencing in any of the ADA-SCID participants. This suggests that further studies are needed to determine the utility of germline analyses in revealing the underlying genetic risk of malignancy in participants who undergo gene therapy. Although these results are promising, larger scale studies are needed to corroborate the effect of ASCT-GT on TL and CHIP. This trial was registered at www.clinicaltrials.gov as #NCT00794508.


Subject(s)
Severe Combined Immunodeficiency , Child , Humans , Busulfan , Clonal Hematopoiesis , Genetic Therapy , Severe Combined Immunodeficiency/genetics
7.
Front Mol Biosci ; 9: 887758, 2022.
Article in English | MEDLINE | ID: mdl-35782872

ABSTRACT

Named the "caretakers" of the genome, RecQ helicases function in several pathways to maintain genomic stability and repair DNA. This highly conserved family of enzymes consist of five different proteins in humans: RECQL1, BLM, WRN, RECQL4, and RECQL5. Biallelic germline mutations in BLM, WRN, and RECQL4 have been linked to rare cancer-predisposing syndromes. Emerging research has also implicated somatic alterations in RecQ helicases in a variety of cancers, including hematological malignancies, breast cancer, osteosarcoma, amongst others. These alterations in RecQ helicases, particularly overexpression, may lead to increased resistance of cancer cells to conventional chemotherapy. Downregulation of these proteins may allow for increased sensitivity to chemotherapy, and, therefore, may be important therapeutic targets. Here we provide a comprehensive review of our current understanding of the role of RecQ DNA helicases in cancer and discuss the potential therapeutic opportunities in targeting these helicases.

8.
Genet Med ; 24(7): 1476-1484, 2022 07.
Article in English | MEDLINE | ID: mdl-35420546

ABSTRACT

PURPOSE: This study aimed to describe the spectrum of cancers observed in Bloom Syndrome and the observed survival and age of first cancer diagnosis in Bloom syndrome as these are not well-defined. METHODS: Data from the Bloom Syndrome Registry (BSR) was used for this study. Cancer history, ages of first cancer diagnosis, and ages of death were compiled from the BSR and analyzed. RESULTS: Among the 290 individuals in the BSR, 155 (53%) participants developed 251 malignant neoplasms; 100 (65%) were diagnosed with 1 malignancy, whereas the remaining 55 (35%) developed multiple malignancies. Of the 251 neoplasms, 83 (33%) were hematologic and 168 (67%) were solid tumors. Hematologic malignancies (leukemia and lymphoma) were more common than any of the solid tumors. The most commonly observed solid tumors were colorectal, breast, and oropharyngeal. The cumulative incidence of any malignancy by age 40 was 83%. The median survival for all participants in the BSR was 36.2 years. There were no significant differences in time to first cancer diagnosis or survival by genotype among the study participants. CONCLUSION: We describe the spectrum of cancers observed in Bloom syndrome and the observed survival and age of first cancer diagnosis in Bloom syndrome. We also highlight the significant differences in survival and age of diagnosis seen among different tumor types and genotypes.


Subject(s)
Bloom Syndrome , Hematologic Neoplasms , Neoplasms , Adult , Bloom Syndrome/diagnosis , Bloom Syndrome/epidemiology , Bloom Syndrome/genetics , Hematologic Neoplasms/diagnosis , Humans , Incidence , Neoplasms/diagnosis , Neoplasms/epidemiology , Registries
9.
Blood ; 139(2): 188-204, 2022 01 13.
Article in English | MEDLINE | ID: mdl-34767029

ABSTRACT

The discovery of novel hematopoietic stem cell (HSC) surface markers can enhance understanding of HSC identity and function. We have discovered a population of primitive bone marrow (BM) HSCs distinguished by their expression of the heparan sulfate proteoglycan Syndecan-2, which serves as both a marker and a regulator of HSC function. Syndecan-2 expression was increased 10-fold in CD150+CD48-CD34-c-Kit+Sca-1+Lineage- cells (long-term HSCs [LT-HSCs]) compared with differentiated hematopoietic cells. Isolation of BM cells based solely on syndecan-2 surface expression produced a 24-fold enrichment for LT-HSCs and sixfold enrichment for α-catulin+c-kit+ HSCs, and yielded HSCs with superior in vivo repopulating capacity compared with CD150+ cells. Competitive repopulation assays revealed the HSC frequency to be 17-fold higher in syndecan-2+CD34-KSL cells compared with syndecan-2-CD34-KSL cells and indistinguishable from CD150+CD34-KSL cells. Syndecan-2 expression also identified nearly all repopulating HSCs within the CD150+CD34-KSL population. Mechanistically, syndecan-2 regulates HSC repopulating capacity through control of expression of Cdkn1c (p57) and HSC quiescence. Loss of syndecan-2 expression caused increased HSC cell cycle entry, downregulation of Cdkn1c, and loss of HSC long-term repopulating capacity. Syndecan-2 is a novel marker of HSCs that regulates HSC repopulating capacity via control of HSC quiescence.


Subject(s)
Hematopoietic Stem Cells/cytology , Syndecan-2/metabolism , Animals , Cell Cycle , Cell Differentiation , Cells, Cultured , Female , Gene Expression Regulation , Hematopoietic Stem Cells/metabolism , Male , Mice , Syndecan-2/genetics
10.
Nat Commun ; 12(1): 6990, 2021 11 30.
Article in English | MEDLINE | ID: mdl-34848712

ABSTRACT

Ionizing radiation and chemotherapy deplete hematopoietic stem cells and damage the vascular niche wherein hematopoietic stem cells reside. Hematopoietic stem cell regeneration requires signaling from an intact bone marrow (BM) vascular niche, but the mechanisms that control BM vascular niche regeneration are poorly understood. We report that BM vascular endothelial cells secrete semaphorin 3 A (SEMA3A) in response to myeloablation and SEMA3A induces p53 - mediated apoptosis in BM endothelial cells via signaling through its receptor, Neuropilin 1 (NRP1), and activation of cyclin dependent kinase 5. Endothelial cell - specific deletion of Nrp1 or Sema3a or administration of anti-NRP1 antibody suppresses BM endothelial cell apoptosis, accelerates BM vascular regeneration and concordantly drives hematopoietic reconstitution in irradiated mice. In response to NRP1 inhibition, BM endothelial cells increase expression and secretion of the Wnt signal amplifying protein, R spondin 2. Systemic administration of anti - R spondin 2 blocks HSC regeneration and hematopoietic reconstitution which otherwise occurrs in response to NRP1 inhibition. SEMA3A - NRP1 signaling promotes BM vascular regression following myelosuppression and therapeutic blockade of SEMA3A - NRP1 signaling in BM endothelial cells accelerates vascular and hematopoietic regeneration in vivo.


Subject(s)
Bone Marrow/metabolism , Hematopoietic Stem Cells/metabolism , Neuropilin-1/genetics , Neuropilin-1/metabolism , Regeneration/physiology , Animals , Apoptosis , Bone Marrow/pathology , Bone Marrow Cells , Cyclin-Dependent Kinase 5/metabolism , Female , Male , Mice , Mice, Inbred C57BL , Semaphorin-3A/metabolism , Signal Transduction , Transcriptome , Wnt Proteins
11.
J Natl Compr Canc Netw ; 19(6): 733-754, 2021 06 30.
Article in English | MEDLINE | ID: mdl-34214968

ABSTRACT

Hodgkin lymphoma (HL) is a highly curable form of cancer, and current treatment regimens are focused on improving treatment efficacy while decreasing the risk of late effects of treatment. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for pediatric HL provide recommendations on the workup, diagnostic evaluation, and treatment of classic HL, including principles of pathology, imaging, staging, systemic therapy, and radiation therapy. This portion of the NCCN Guidelines focuses on the management of pediatric classic HL in the upfront and relapsed/refractory settings.


Subject(s)
Hodgkin Disease , Child , Hodgkin Disease/diagnosis , Hodgkin Disease/pathology , Hodgkin Disease/therapy , Humans , Medical Oncology , Treatment Outcome
12.
Am J Med Genet A ; 185(5): 1430-1436, 2021 05.
Article in English | MEDLINE | ID: mdl-33683022

ABSTRACT

Activating variants in the platelet-derived growth factor receptor ß gene (PDGFRB) have been associated with Kosaki overgrowth syndrome, infantile myofibromatosis, and Penttinen premature aging syndrome. A recently described phenotype with fusiform aneurysm has been associated with mosaic PDGFRB c.1685A > G p.(Tyr562Cys) variant. Few reports however have examined the vascular phenotypes and mosaic effects of PDGFRB variants. We describe clinical characteristics of two patients with a recurrent mosaic PDGFRB p.(Tyr562Cys) variant identified via next-generation sequencing-based genetic testing. We observed intracranial fusiform aneurysm in one patient and found an additional eight patients with aneurysms and phenotypes associated with PDGFRB-activating variants through literature search. The conditions caused by PDGFRB-activating variants share overlapping features including overgrowth, premature aged skin, and vascular malformations including aneurysms. Aneurysms are progressive and can result in morbidities and mortalities in the absence of successful intervention. Germline and/or somatic testing for PDGFRB gene should be obtained when PDGFRB activating variant-related phenotypes are present. Whole-body imaging of the arterial tree and echocardiography are recommended after diagnosis. Repeating the imaging study within a 6- to 12-month period after detection is reasonable. Finally, further evaluation for the effectiveness and safety profile of kinase inhibitors in this patient population is warranted.


Subject(s)
Aneurysm/genetics , Growth Disorders/genetics , Intracranial Aneurysm/genetics , Receptor, Platelet-Derived Growth Factor beta/genetics , Adult , Aging, Premature/genetics , Aneurysm/epidemiology , Aneurysm/pathology , Child , Female , Genetic Predisposition to Disease , Germ-Line Mutation/genetics , Growth Disorders/epidemiology , Growth Disorders/pathology , High-Throughput Nucleotide Sequencing , Humans , Infant , Intracranial Aneurysm/epidemiology , Intracranial Aneurysm/pathology , Male , Middle Aged , Mosaicism , Phenotype , Skin Abnormalities/epidemiology , Skin Abnormalities/genetics , Skin Abnormalities/pathology , Young Adult
13.
Blood ; 136(4): 441-454, 2020 07 23.
Article in English | MEDLINE | ID: mdl-32369572

ABSTRACT

Chemotherapy and irradiation cause DNA damage to hematopoietic stem cells (HSCs), leading to HSC depletion and dysfunction and the risk of malignant transformation over time. Extrinsic regulation of HSC DNA repair is not well understood, and therapies to augment HSC DNA repair following myelosuppression remain undeveloped. We report that epidermal growth factor receptor (EGFR) regulates DNA repair in HSCs following irradiation via activation of the DNA-dependent protein kinase-catalytic subunit (DNA-PKcs) and nonhomologous end joining (NHEJ). We show that hematopoietic regeneration in vivo following total body irradiation is dependent upon EGFR-mediated repair of DNA damage via activation of DNA-PKcs. Conditional deletion of EGFR in hematopoietic stem and progenitor cells (HSPCs) significantly decreased DNA-PKcs activity following irradiation, causing increased HSC DNA damage and depressed HSC recovery over time. Systemic administration of epidermal growth factor (EGF) promoted HSC DNA repair and rapid hematologic recovery in chemotherapy-treated mice and had no effect on acute myeloid leukemia growth in vivo. Further, EGF treatment drove the recovery of human HSCs capable of multilineage in vivo repopulation following radiation injury. Whole-genome sequencing analysis revealed no increase in coding region mutations in HSPCs from EGF-treated mice, but increased intergenic copy number variant mutations were detected. These studies demonstrate that EGF promotes HSC DNA repair and hematopoietic regeneration in vivo via augmentation of NHEJ. EGF has therapeutic potential to promote human hematopoietic regeneration, and further studies are warranted to assess long-term hematopoietic effects.


Subject(s)
DNA End-Joining Repair , ErbB Receptors/metabolism , Hematopoiesis/physiology , Hematopoietic Stem Cells/metabolism , Regeneration , Animals , Calcium-Binding Proteins/genetics , Calcium-Binding Proteins/metabolism , DNA Damage , DNA-Activated Protein Kinase/genetics , DNA-Activated Protein Kinase/metabolism , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Epidermal Growth Factor/genetics , Epidermal Growth Factor/metabolism , ErbB Receptors/genetics , Hematopoietic Stem Cells/cytology , Humans , Mice
14.
Insect Biochem Mol Biol ; 121: 103365, 2020 06.
Article in English | MEDLINE | ID: mdl-32247760

ABSTRACT

The short days of late summer and early fall are the environmental cues that most temperate insects and other animals use to predict winter's arrival. Although it is still unclear precisely how insects measure daylength, there is mounting evidence that the circadian clock regulates seasonal responses including photoperiodic diapause. Females of the Northern house mosquito, Culex pipiens, enter an adult reproductive diapause in response to short daylengths. While in this state, females divert their resources from reproduction to survival, arresting egg follicle development and increasing fat content. Here, we characterized the expression profile of two circadian transcription factors, vrille (vri) and Par domain protein 1 (Pdp1), as well as genes downstream of the clock, takeout (to) and Nocturnin (Noc) and under different seasonal conditions. We saw that while vri mRNA oscillated under both long day and short day conditions, Pdp1 expression oscillated only under long day conditions and was constitutively upregulated in diapausing females. We saw similar expression profiles for to and Noc, suggesting that PDP1 might regulate their expression or that Pdp1, to and Noc might be regulated by the same transcription factor. We suppressed vri and Pdp1 using RNA interference. dsRNA against vri provided inconsistent results, sometimes stimulating autogenous egg follicle development in both long and short day-reared females, and other times had no effect. In contrast, knocking down Pdp1 prevented short day-reared females from accumulating fat reserves, but increased expression of to and Noc. Taken together, these data suggest that the circadian transcription factors Vri and Pdp1 may independently regulate signaling pathways underlying arrested egg follicle development and fat accumulation in diapausing females of Cx. pipiens.


Subject(s)
Circadian Clocks/genetics , Culex/physiology , Diapause, Insect/genetics , Insect Proteins/genetics , Transcription Factors/genetics , Animals , Culex/genetics , Female , Insect Proteins/metabolism , Seasons , Transcription Factors/metabolism
16.
Am J Med Genet A ; 179(12): 2517-2531, 2019 12.
Article in English | MEDLINE | ID: mdl-31639285

ABSTRACT

The hedgehog (Hh) pathway is highly conserved and required for embryonic patterning and determination. Mutations in the Hh pathway are observed in sporadic tumors as well as under syndromic conditions. Common to these syndromes are the findings of polydactyly/syndactyly and brain overgrowth. The latter is also a finding most commonly observed in the cases of mutations in the PI3K/AKT/mTOR pathway. We have identified novel Hh pathway mutations and structural copy number variations in individuals with somatic overgrowth, macrocephaly, dysmorphic facial features, and developmental delay, which phenotypically closely resemble patients with phosphatase and tensin homolog (PTEN) mutations. We hypothesized that brain overgrowth and phenotypic overlap with syndromic overgrowth syndromes in these cases may be due to crosstalk between the Hh and PI3K/AKT/mTOR pathways. To test this, we modeled disease-associated variants by generating PTCH1 and Suppressor of Fused (SUFU) heterozygote cell lines using the CRISPR/Cas9 system. These cells demonstrate activation of PI3K signaling and increased phosphorylation of its downstream target p4EBP1 as well as a distinct cellular phenotype. To further investigate the mechanism underlying this crosstalk, we treated human neural stem cells with sonic hedgehog (SHH) ligand and performed transcriptional analysis of components of the mTOR pathway. These studies identified decreased expression of a set of mTOR negative regulators, leading to its activation. We conclude that there is a significant crosstalk between the SHH and PI3K/AKT/mTOR. We propose that this crosstalk is responsible for why mutations in PTCH1 and SUFU lead to macrocephaly phenotypes similar to those observed in PTEN hamartoma and other overgrowth syndromes associated with mutations in PI3K/AKT/mTOR pathway genes.


Subject(s)
Hedgehog Proteins/metabolism , Megalencephaly/genetics , Megalencephaly/metabolism , Mutation , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction , TOR Serine-Threonine Kinases/metabolism , CRISPR-Cas Systems , Cell Line , Child, Preschool , Female , Gene Deletion , Haploinsufficiency , Humans , Infant , Male , Megalencephaly/diagnosis , Models, Biological , Neural Stem Cells
17.
Cancer Genet ; 239: 33-35, 2019 11.
Article in English | MEDLINE | ID: mdl-31520998

ABSTRACT

Familial adenomatous polyposis (FAP) is an autosomal dominant condition that predisposes to multiple malignancies, most commonly colorectal carcinoma, but has rarely been associated with lymphoma. We discuss one patient found to have Burkitt-like Lymphoma (BLL) with 11q aberration in the setting of previously undiagnosed FAP. We review the literature of FAP and associated malignancies and the provisional WHO classification of Burkitt-like lymphoma with 11q aberration. Both FAP and Burkitt-like lymphoma with 11q aberration involve perturbation of the MYC network and this may provide insight into a connection between these two diagnoses. However, further study is needed to elucidate if there is an increased risk of BLL and other subtypes of lymphoma among patients with FAP in order to provide optimal counseling and surveillance for patients with FAP.


Subject(s)
Adenomatous Polyposis Coli , Burkitt Lymphoma , Abdomen/diagnostic imaging , Abdomen/pathology , Adenomatous Polyposis Coli/complications , Adenomatous Polyposis Coli/diagnosis , Adenomatous Polyposis Coli/genetics , Adolescent , Burkitt Lymphoma/complications , Burkitt Lymphoma/diagnosis , Burkitt Lymphoma/genetics , Chromosome Aberrations , Humans , Male
18.
Genet Med ; 21(12): 2723-2733, 2019 12.
Article in English | MEDLINE | ID: mdl-31239556

ABSTRACT

PURPOSE: Pathogenic variants in the chromatin organizer CTCF were previously reported in seven individuals with a neurodevelopmental disorder (NDD). METHODS: Through international collaboration we collected data from 39 subjects with variants in CTCF. We performed transcriptome analysis on RNA from blood samples and utilized Drosophila melanogaster to investigate the impact of Ctcf dosage alteration on nervous system development and function. RESULTS: The individuals in our cohort carried 2 deletions, 8 likely gene-disruptive, 2 splice-site, and 20 different missense variants, most of them de novo. Two cases were familial. The associated phenotype was of variable severity extending from mild developmental delay or normal IQ to severe intellectual disability. Feeding difficulties and behavioral abnormalities were common, and variable other findings including growth restriction and cardiac defects were observed. RNA-sequencing in five individuals identified 3828 deregulated genes enriched for known NDD genes and biological processes such as transcriptional regulation. Ctcf dosage alteration in Drosophila resulted in impaired gross neurological functioning and learning and memory deficits. CONCLUSION: We significantly broaden the mutational and clinical spectrum ofCTCF-associated NDDs. Our data shed light onto the functional role of CTCF by identifying deregulated genes and show that Ctcf alterations result in nervous system defects in Drosophila.


Subject(s)
CCCTC-Binding Factor/genetics , CCCTC-Binding Factor/metabolism , Neurodevelopmental Disorders/genetics , Animals , Child , Chromatin/genetics , Chromatin/metabolism , Developmental Disabilities/genetics , Drosophila Proteins/genetics , Drosophila Proteins/metabolism , Drosophila melanogaster/genetics , Drosophila melanogaster/metabolism , Female , Gene Expression Profiling/methods , Gene Expression Regulation/genetics , Humans , Intellectual Disability/genetics , Male , Mutation/genetics , Mutation, Missense/genetics , Neurodevelopmental Disorders/metabolism , Transcription Factors/genetics , Exome Sequencing/methods , Young Adult
19.
Mol Genet Genomic Med ; 7(7): e00725, 2019 07.
Article in English | MEDLINE | ID: mdl-31197971

ABSTRACT

BACKGROUND: Polycystic kidney disease (PKD) is an inherited condition characterized by progressive development of end-stage renal disease, hypertension, hepatic fibrosis, and cysts in the kidney, liver, pancreas, spleen, thyroid, and epididymis. While malignancies have been reported in association with PKD in adults, the incidence of malignancies in children with PKD is not currently known. METHODS: We report on five patients with a known history of PKD who developed a malignancy as children at the University of California, Los Angeles and the University of Colorado Anschutz Medical Campus. Patients were included from 2012 to 2017. RESULTS: We present five patients with a history of PKD diagnosed with a malignancy during childhood without any additional known mutations to suggest a genetic predisposition to develop cancer. This includes the first reported case of hepatocellular carcinoma in a patient with autosomal recessive polycystic kidney disease. CONCLUSION: Our report illustrates the potential that PKD may be associated with an increased risk for developing cancer, even in children. Further research is necessary to better understand this relationship.


Subject(s)
Genetic Predisposition to Disease , Neoplasms/genetics , Polycystic Kidney Diseases/complications , Adolescent , Child , Female , Humans , Infant , Male , Neoplasms/complications , Neoplasms/pathology , Polycystic Kidney Diseases/genetics , Polycystic Kidney Diseases/pathology , Receptors, Cell Surface/genetics , TRPP Cation Channels/genetics
20.
Cell Stem Cell ; 23(3): 370-381.e5, 2018 09 06.
Article in English | MEDLINE | ID: mdl-30100167

ABSTRACT

Bone marrow (BM) perivascular stromal cells and vascular endothelial cells (ECs) are essential for hematopoietic stem cell (HSC) maintenance, but the roles of distinct niche compartments during HSC regeneration are less understood. Here we show that Leptin receptor-expressing (LepR+) BM stromal cells and ECs dichotomously regulate HSC maintenance and regeneration via secretion of pleiotrophin (PTN). BM stromal cells are the key source of PTN during steady-state hematopoiesis because its deletion from stromal cells, but not hematopoietic cells, osteoblasts, or ECs, depletes the HSC pool. Following myelosuppressive irradiation, PTN expression is increased in bone marrow endothelial cells (BMECs), and PTN+ ECs are more frequent in the niche. Moreover, deleting Ptn from ECs impairs HSC regeneration whereas Ptn deletion from BM stromal cells does not. These findings reveal dichotomous and complementary regulation of HSC maintenance and regeneration by BM stromal cells and ECs.


Subject(s)
Bone Marrow/metabolism , Carrier Proteins/metabolism , Cell Self Renewal , Cytokines/metabolism , Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/metabolism , Animals , Cytokines/deficiency , Female , Male , Mice , Mice, Inbred C57BL
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