Josef T Prchal

University of Utah, Salt Lake City, Utah, United States

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Publications (380)2838.61 Total impact

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    ABSTRACT: Key message: Human gain-of-function EPOR (mtHEPOR) causes fetal polycythemia in knock-in mice. Wild-type human EPOR causes fetal anemia in knock-in mouse model. mtHEPOR mice have delayed switch from primitive to definitive erythropoiesis. Polycythemia of mtHEPOR mice is transiently corrected in perinatal life. mtHEPOR newborns have low Epo and increased exposure of erythrocytes' phosphatidylserine.
    No preview · Article · Dec 2015 · Journal of Molecular Medicine
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    Full-text · Poster · Dec 2015
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    Full-text · Poster · Dec 2015
  • Linghua Wang · David A. Wheeler · Josef T. Prchal
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    ABSTRACT: Acquired uniparental disomy (aUPD) is a common and recurrent molecular event in human cancers, which leads to homozygosity for tumor suppressor genes as well as oncogenes, while retaining diploid chromosomal complement. Due to the lack of copy number change, aUPD is undetectable by comparative genome hybridization so the magnitude of this genetic change was underappreciated in the past. 9p aUPD was first described in 2002 in polycythemia vera (PV) patients. Since then, systematic application of genome-wide single nucleotide polymorphism arrays has demonstrated that 9p aUPD is the most common chromosomal aberration in myeloproliferative neoplasms (MPN) contributing to discovery of PV-defining mutation JAK2(V617F). It was also found in other myeloid and lymphoid malignancies, though at a relatively lower frequency. By leading to JAK2(V617F) homozygosity, 9p aUPD plays a causal role in the development of PV and is also associated with less favorable clinical outcome. It is also possible that new targets other than JAK2(V617F) are present within 9p aUPD, which may contribute to diversity of PV outcome and phenotype. This review will summarize recent discoveries on 9p aUPD in hematological malignancies; discuss possible underlying mechanisms and potential roles of 9p aUPD in the PV pathogenesis, the relationship between 9p aUPD and JAK2(V617F), and the possible new cancer-related targets within 9p aUPD region.
    No preview · Article · Dec 2015 · Experimental hematology
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    Preview · Article · Nov 2015
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    ABSTRACT: Some native Tibetan, Andean and Ethiopian populations have lived at altitudes ranging from 3000 to >4000 m above sea level for hundreds of generations and exhibit distinct combinations of traits at altitude. It was long hypothesized that genetic factors contribute to adaptive differences in these populations, and recent advances in genomics provide evidence that some of the strongest signatures of positive selection in humans are those identified in Tibetans. Many of the top adaptive genomic regions highlighted thus far harbour genes related to hypoxia sensing and response. Putatively adaptive copies of three hypoxia-inducible factor pathway genes, EPAS1, EGLN1 and PPARA, are associated with sea-level range, rather than elevated, haemoglobin concentration observed in many Tibetans at high altitude, and recent studies provide insight into some of the precise adaptive variants, timing of adaptive events and functional roles. While several studies in highland Tibetans have converged on a few hypoxia-inducible factor pathway genes, additional candidates have been reported in independent studies of Tibetans located throughout the Qinghai-Tibetan Plateau. Various aspects of adaptive significance have yet to be identified, integrated, and fully explored. Given the rapid technological advances and interdisciplinary efforts in genomics, physiology and molecular biology, careful examination of Tibetans and comparisons with other distinctively adapted highland populations will provide valuable insight into evolutionary processes and models for both basic and clinical research.
    No preview · Article · Oct 2015 · Experimental physiology
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    ABSTRACT: We recently described a novel, non-inherited syndrome of tumor-specific mutations of hypoxia-inducible factor 2α, encoded by EPAS1, leading to formation of multiple paragangliomas and somatostatinomas in the setting of congenital polycythemia. Although we had suspected that somatic mosaicism of EPAS1 mutations was the underlying cause of tumorigenesis, we could not validate this theory in our initial findings. In this report, we developed a sensitive, peptide nucleic acid sequencing assay to uncover the presence of EPAS1 mutations in blood and other somatic tissues of the two patients who were described in the initial characterization of this syndrome. As such, the current study demonstrates that the underlying pathogenesis of the syndrome of multiple paraganglioma and somatostatinoma formation with congenital polycythemia is somatic mosaicism of EPAS1 mutations.
    Preview · Article · Oct 2015
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    ABSTRACT: The frequency of coexisting JAK2(V617F)/MPL and JAK2(V617F)/JAK2 exon-12 mutations has not been previously investigated in MPNs. Poor survival was reported in primary myelofibrosis with low JAK2(V617F) allelic burden. However, mutational status of JAK2 exon-12 or MPL were not reported in these patients. We developed a cost-effective multiplex high resolution melt assay that screens for mutations in JAK2 gene exons-12 and -14 ((V617F)) and MPL gene exon-10. Coexisting mutations with JAK2(V617F) were detected in 2.9% (6/208; two JAK2 exon-12, and four MPL exon-10) patient specimens with known JAK2(V617F) (allelic-burden range: 0.1-96.8%). Coexisting mutations were detected in specimens with <12% JAK2(V617F) allelic burden. Current WHO guidelines, do not recommend further testing once JAK2(V617F) mutation detected in MPNs. Our findings, however, indicate that quantification of JAK2(V617F) allele burden may be clinically relevant in MPNs, and in those with low allelic burden additional testing for JAK2 exon-12 and MPL exon-10 mutation should be pursued.
    No preview · Article · Sep 2015 · Leukemia and Lymphoma
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    ABSTRACT: Background: End-tidal breath carbon monoxide (ETCOc) levels correlate with catabolism of heme, but until recently, this measurement was not readily available for application to neonatology practice. Objectives: We performed a prospective, multihospital, test-of-concept study where ETCOc was measured during the birth hospitalization of neonates with a total bilirubin (TB) value >75th percentile on the Bhutani bilirubin nomogram. This was done to test the feasibility and ease of use of this new device. Methods: Neonates with an elevated ETCOc (with a >95th percentile reference interval previously established) were labeled as having 'hemolytic jaundice'. We recommended a follow-up TB check <24 h after hospital discharge to these families. Results: One hundred and fifteen neonates were eligible for the study, the parents of 103 provided consent, and measurements were obtained for 100. Sixty-three had normal and 37 had elevated ETCOc values. By means of a direct antiglobulin test (DAT; Coombs), 11 of these 37 were found positive for ABO hemolytic disease; the remaining 26 had other etiologies. Thirty-six of the 37 with an elevated ETCOc had repeat TB monitoring <24 h after discharge home. None of the 100 were rehospitalized for jaundice treatment compared with a rate of 2.99 rehospitalizations per 100 control neonates who had a TB value >75th percentile (p = 0.079). Conclusion: ETCOc measurement is a feasible means of assessing hemolysis in jaundiced neonates during the birth hospitalization. When hemolysis is identified, parents are likely to comply with instructions to bring the infant for a TB checkup <24 h after discharge home.
    No preview · Article · Sep 2015 · Neonatology
  • S Swierczek · L T Lima · T Tashi · S J Kim · X T Gregg · J T Prchal
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    ABSTRACT: Leukemia is one of the leading journals in hematology and oncology. It is published monthly and covers all aspects of the research and treatment of leukemia and allied diseases. Studies of normal hemopoiesis are covered because of their comparative relevance.
    No preview · Article · Sep 2015 · Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
  • Josef T Prchal

    No preview · Article · Aug 2015 · Proceedings of the National Academy of Sciences
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    Full-text · Article · Jul 2015 · Mayo Clinic Proceedings
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    ABSTRACT: Interferon alpha (IFNα) is used clinically to restore polyclonal hematopoiesis in patients with the myeloproliferative neoplasms (MPN) polycythemia vera (PV) and essential thrombocythemia (ET), and to improve chemosensitivity in chronic myeloid leukemia patients. However, the mechanisms by which IFNα affects disease-initiating hematopoietic stem and progenitor cells (HSPCs) remain poorly understood. While IFNα has been shown to transiently impair quiescence of murine hematopoietic stem cells, its effects on human HSPCs have not been studied in vivo. Here, we compared bone marrow serially obtained from MPN patients before and during pegylated IFNα (Peg-IFNα) treatment against marrow serially obtained from patients on hydroxyurea. The percentage of HSPCs actively undergoing cell cycle was increased after Peg-IFNα treatment in a majority of patients compared to hydroxyurea-treated controls, suggesting that IFNα promotes cell division. Furthermore, transcriptional profiling revealed that cell cycle-associated genes were induced, while genes involved in HSPC quiescence were repressed during IFNα treatment. Compared to hydroxyurea-treated controls, Peg-IFNα treated patients had similar HSPC numbers but increased numbers of hematopoietic progenitors as determined by colony formation assay, indicating an increase in myeloid proliferation/differentiation. These effects occurred regardless of JAK2 mutational status. Together, these data provide the first in vivo evidence that Peg-IFNα promotes cell division and differentiation of human HSPCs. Copyright © 2015 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.
    No preview · Article · Jun 2015 · Experimental hematology
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    ABSTRACT: Recent studies have identified genes involved in high-altitude adaptation in Tibetans. Three of these genes (EPAS1, EGLN1, and PPARA) are associated with decreased hemoglobin (Hb) levels compared to non-Tibetans living at altitude. Consistent with the phenotype, EGLN1 in Tibetans has a gain of function mutation that confers a higher affinity for oxygen, hence less sensitivity to hypoxia. Considering the demands imposed upon metabolism in meeting energy demands despite limitations on fuel oxidation, we hypothesized that other selected genes might alter metabolism to allow adaptation to altitude despite the desensitization of the upstream hypoxia sensing caused by the EGLN1 mutation that results in the failure to sense hypoxia. A shift in fuel preference to glucose oxidation and glycolysis at the expense of fatty acid oxidation would provide adaptation to decreased oxygen availability. Measurements of serum metabolites from Tibetans living at high altitude are consistent with this hypothesis: The EPAS1 haplotype is significantly associated with increased lactate levels (suggesting increased anaerobic metabolism), and the PPARA haplotype and serum free fatty acids are positively related (suggesting decreased fat oxidation). These data suggest that the high altitude adaptations may offer protection from diabetes at high altitude but increase diabetes risk at lower elevations and/or with adoption of a nontraditional diet. It should also be considered in future work in the field that because iron is a cofactor for EGLN1, there may be significant associations of phenotypes with the significant degrees of variation seen in tissue iron among human populations. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    No preview · Article · Jun 2015 · Experimental physiology
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    ABSTRACT: During prolonged hypoxia, hypoxia-inducible factors (HIFs) mediate an increase in erythropoiesis, leading to an increased red blood cell (RBC) mass and polycythemia. Upon return to normoxia, the increased RBC mass is abruptly overcorrected by the preferential destruction of hypoxia-formed young RBCs, a phenomenon termed neocytolysis. The molecular and biochemical mechanisms involved in neocytolysis are unknown. We developed a murine model of neocytolysis by exposing mice to 12 % oxygen for 10 days followed by return to normoxia. Upon return to normoxia, there was excessive accumulation of reactive oxygen species (ROS) in RBCs from an increased reticulocyte mitochondrial mass correlating with decreased Bnip3L transcripts (Bnip3L mediates reticulocyte mitophagy) and reduced catalase activity. During hypoxia, upregulated miR-21 resulted in low catalase activity in young RBCs. Furthermore, neocytolysis was attenuated by antioxidants and plasma catalase and blunted in mice that had constitutively high expression of HIFs. Among human neonates studied, we report data supporting the existence of neocytolysis during the first week of life. Together, these experiments indicate that the major mechanisms causing neocytolysis involve (1) production of young RBCs with low catalase during hypoxia and (2) lysis of the young RBCs after return to normoxia, mediated by ROS from an increased mitochondrial mass. We report a mouse model of neocytolysis. Neocytolysis is caused by excessive ROS formation mediated by HIF. ROS is generated from increased mitochondria in reticulocytes. Hypoxia-generated RBCs have low catalase and are preferentially destroyed. Reduced catalase is regulated by increased microRNA-21.
    Full-text · Article · May 2015 · Journal of Molecular Medicine
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    ABSTRACT: Activation of JAK2, frequently as a result of the JAK2(V617F) mutation, is a characteristic feature of the classical myeloproliferative neoplasms (MPN) polycythemia vera, essential thrombocythemia and myelofibrosis and is thought to be responsible for the constitutional symptoms associated with these diseases. BMS-911543 is a JAK2 selective inhibitor that induces apoptosis in JAK2-dependent cell lines and inhibits the growth of CD34(+) progenitor cells from patients with JAK2(V617F) - positive MPN. To explore the clinical potential of this inhibitor, we tested BMS-911543 in a murine retroviral transduction - transplantation model of JAK2(V617F) MPN. Treatment was initiated at two dose levels (3 mg/kg and 10 mg/kg) when the hematocrit exceeded 70%. Following the first week, white blood cell counts were reduced to normal in the high dose group and were maintained well below the vehicle-treated mice throughout the study. However, BMS-911543 had no effect on red blood cell parameters. After 42 days of treatment, the proportion of JAK2(V617F) - positive cells in hematopoietic tissues was identical or slightly increased compared to controls. Plasma concentrations of IL-6, IL-15, and TNFα were elevated in MPN mice and reduced in the high dose treatment group, while other cytokines were unchanged. Inhibitor activity after dosing was confirmed in a cell culture assay using the plasma of dosed mice and pSTAT5 flow cytometry. Collectively, these results show that BMS-911543 has limited activity in this murine model of JAK2(V617F) - driven MPN and suggest that targeting JAK2 alone may be insufficient to achieve effective disease control. Copyright © 2015 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Apr 2015 · Experimental hematology
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    ABSTRACT: The classical Philadelphia chromosome-negative myeloproliferative neoplasms (MPN), which include essential thrombocythemia, polycythemia vera, and myelofibrosis (MF), are in a new era of molecular diagnosis, ushered in by the identification of the JAK2(V617F) and cMPL mutations in 2005 and 2006, respectively, and the CALR mutations in 2013. Coupled with increased knowledge of disease pathogenesis and refined diagnostic criteria and prognostic scoring systems, a more nuanced appreciation has emerged of the burden of MPN in the United States, including the prevalence, symptom burden, and impact on quality of life. Biological advances in MPN have translated into the rapid development of novel therapeutics, culminating in the approval of the first treatment for MF, the JAK1/JAK2 inhibitor ruxolitinib. However, certain practical aspects of care, such as those regarding diagnosis, prevention of vascular events, choice of cytoreductive agent, and planning for therapies, present challenges for hematologists/oncologists, and are discussed in this article. Copyright © 2015 by the National Comprehensive Cancer Network.
    No preview · Article · Apr 2015 · Journal of the National Comprehensive Cancer Network: JNCCN

  • No preview · Article · Jan 2015 · Blood
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    ABSTRACT: ABSTRACT We performed a multicenter, investigator initiated, phase I dose escalation study of the oral multi-kinase inhibitor lestaurtinib in patients with JAK2V617F positive myelofibrosis, irrespective of baseline platelet count. A total of 34 patients were enrolled. DLTs were observed in 3 patients overall, at the 100 mg (1) and 160 mg (2) twice daily dose levels. The MTD was 140 mg twice daily. Gastrointestinal toxicity was the most common adverse event.. Sixteen patients were evaluable for response at 12 weeks; 7 patients had clinical improvement by IWG-MRT criteria. Meaningful reductions in JAK2 V617F allele burden were not observed. To measure JAK2 inhibition in vivo, plasma from treated patients was assayed for its ability to inhibit phosphorylation of STAT5: doses lower than 140 mg had variable and incomplete inhibition. In this phase I study, although gastrointestinal adverse events were common, significant clinical activity with lestaurtinib was observed. [NCT00668421].
    No preview · Article · Jan 2015 · Leukemia and Lymphoma
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    ABSTRACT: Evaluation of bone marrow fibrosis in myeloproliferative neoplasms (MPN) is subject to interobserver inconsistency, and cutpoints for determination of therapy are dependent on manual pathologist grading of reticulin. To provide a more consistent approach to cutpoint determination, we developed a stereologybased method of calculating length fiber density (the length of the fiber network divided by the volume of bone marrow hematopoietic tissue). Forty-eight thin needle core bone marrow biopsy samples from patients with MPN were obtained from the University of Utah archives after institutional review board approval and stained for reticulin and then scanned using whole slide imaging. To determine interpathologist concordance, the blinded cases were scored according to the European consensus system by four pathologists. Two pathologists scored twice with a 1-month washout period to determine intrapathologist concordance. Using systematic uniform random sampling and line counting, two techniques adapted from the stereology field, the length density of the reticulin network was measured as well as a measure of heterogeneity across the bone marrow sample. Image analysis was used to measure the area of the reticulin fiber as a two-dimensional profile. To build a model for predicting scoring by stereology, 16 samples were chosen randomly and a linear regression relationship determined. This score was then rounded to 0, 1, 2, or 3, and concordance rates between pathologists and between pathologist and the computer stereology score determined. Results: In the 48 patient cohort, stereology assessment was well correlated with the average of manual pathologist scoring (linear regression, R2=0.7038). While the European consensus scoring system ranges from 0 to 3, the cutpoint between 0/1 and 2/3 is generally used for guiding therapeutic decision as myelofibrosis. In 7 of the 48 cases (15%), pathologists had differing scores across this cutpoint, meaning that the ultimate therapeutic outcome would have been impacted. The stereology score differed with the average of the pathologist scores in only 5 of the 48 cases across this cutpoint (10%). Precision rates for the stereology analysis were 92%, compared with interpathologist concordance ranging from 54.2 to 65.2% and intrapathologist at 60.9%. Computer-based stereology proved to be more reproducible at predicting therapeutic cutpoint than manual scoring. The new technique can be run using standard histochemistry and provides both a nonbiased systematic measure of reticulin and a new measure of reticulin heterogeneity.
    No preview · Article · Jan 2015 · Methods in Pharmacology and Toxicology

Publication Stats

12k Citations
2,838.61 Total Impact Points

Institutions

  • 2006-2015
    • University of Utah
      • • Department of Internal Medicine
      • • School of Medicine
      • • Division of Hematology
      Salt Lake City, Utah, United States
  • 2011
    • The Children's Hospital of Philadelphia
      • Center for Applied Genomics
      Philadelphia, PA, United States
  • 2005-2010
    • Charles University in Prague
      • Department of Pathophysiology (2. LF)
      Praha, Praha, Czech Republic
    • Boston Children's Hospital
      Boston, Massachusetts, United States
    • Johns Hopkins University
      Baltimore, Maryland, United States
  • 2007
    • University of Illinois at Chicago
      • Department of Medicine (Chicago)
      Chicago, Illinois, United States
    • Stanford University
      • Department of Medicine
      Stanford, CA, United States
    • Belfast Healthy Cities
      Béal Feirste, Northern Ireland, United Kingdom
  • 2001-2007
    • Baylor College of Medicine
      • Department of Medicine
      Houston, Texas, United States
  • 2005-2006
    • Howard University
      • Center for Sickle Cell Disease
      Washington, West Virginia, United States
  • 2004-2005
    • Palacký University of Olomouc
      • Department of Pediatrics
      Olmütz, Olomoucký, Czech Republic
  • 2003
    • Texas Children's Cancer and Hematology Centers
      Houston, Texas, United States
  • 2002
    • Rochester General Hospital
      Rochester, New York, United States
  • 1978-2001
    • University of Alabama at Birmingham
      • • Division of Hematology / Oncology
      • • Department of Medicine
      • • Department of Microbiology
      • • Division of Laboratory Medicine
      • • Department of Ophthalmology
      Birmingham, Alabama, United States
  • 2000
    • University of Washington Seattle
      • Division of Oncology
      Seattle, Washington, United States
  • 1997
    • Harvard Medical School
      • Department of Pathology
      Boston, Massachusetts, United States
    • George Washington University
      • Department of Medicine
      Washington, Washington, D.C., United States
  • 1996
    • Cooper Hospital
      Green Bay, Wisconsin, United States
  • 1994
    • The Police Academy of the Czech Republic in Prague
      Praha, Praha, Czech Republic
  • 1981-1994
    • University of Alabama
      Tuscaloosa, Alabama, United States
    • College of Saint Elizabeth
      Boston, Massachusetts, United States
  • 1982-1991
    • St. Elizabeth Hospital
      Louisiana, United States
  • 1989
    • CUNY Graduate Center
      New York, New York, United States
  • 1988
    • City of Hope National Medical Center
      • Department of Molecular Medicine
      Дуарте, California, United States