2002 — 2006 |
Crispino, John D |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Eps: a Novel Hematopoietic Transcription Factor
DESCRIPTION (provided by applicant): EPS (Erythroid Partner of SCL/tal-l) is a novel protein that interacts with the basic Helix aboutLoop-Helix (bHLH) family transcription factors SCL/tal-1 (Stem Cell Leukemia) and E12. EPS is expressed at the onset of yolk sac erythropoiesis in the developing mouse embryo, and enriched in the fetal liver, the site of definitive hematopoiesis, by E12.5. In adult mice, EPS is expressed in the spleen, lung and testis, as well as in all hematopoietic cells, including erythroid, megakaryocyte, myeloid and lymphoid cells. EPS acts as a transcriptional repressor when expressed in yeast, likely via an interaction with the co-repressors Sin3p and Rpd3p. Further studies demonstrated that over-expression of EPS in an erythroid cell line enhances GATA- 1 mediated terminal differentiation. Together these data suggest that EPS is a novel repressor of the SCLTE-protein heterodimers in hematopoietic cells that promotes erythroid cell differentiation. In this application, we propose to further characterize the role of this protein in hematopoiesis. Specifically, we plan to 1) Investigate the ability of EPS to repress transcription through histone deacetylases; 2) Analyze the key functional domains in EPS that are required for the promotion of erythroid cell differentiation, and identify EPS interacting proteins in these cells; and 3) Determine the role of EPS in vivo, by analysis of EPS-deficient embryos. Preliminary results indicate that EPS-deficient mice die in embryogenesis, as would be expected for an essential regulator of blood cell production. A more detailed assessment of the role of EPS in hematopoiesis will assist in our understanding of the role of lineage specific transcription factors in normal blood cell development, and may shed light into the mechanisms by which aberrant expression of these factors promote leukemia.
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1 |
2003 — 2021 |
Crispino, John D |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Mechanisms of Leukemogenesis in Down Syndrome
[unreadable] DESCRIPTION (provided by applicant): Children with Down syndrome (DS) have a 10-20 fold increased risk of developing leukemia, in particular acute megakaryoblastic leukemia (AMKL). While the genetic lesions that promote leukemia in Down syndrome have been largely undefined, we recently demonstrated that leukemic cells from every DS-AMKL patient examined harbor mutations in the essential hematopoietic transcription factor gene GATA1. In every instance, the mutation involved a small insertion or deletion in GATA1 that resulted in a frame-shift and the introduction of a premature stop codon within the sequences encoding the N-terminal activation domain of GATA-1. These mutations prevent the synthesis of the 50-kD full length GATA-1, but not of a 40-kD isoform initiated further downstream, termed GATA-1s. In this application, we propose to study the mechanism of leukemogenesis in patients with GATA1 mutations. Furthermore, we will seek to identify the cooperating factors that are likely contributed by trisomy 21 in Down syndrome AMKL. Specifically, we plan: 1) To determine the incidence and distribution of GATA1 mutations in a greater number of DS-AMKL samples as well as in DNA from patients with DS pre-leukemia, named Transient Myeloproliferative Disorder; 2) To assess whether loss of GATA-1 in conjunction with the mouse equivalent of trisomy 21 can promote leukemogenesis in mice, and further, whether overexpression of GATA-1s can promote immortalization of GATA-1-deficient megakaryocyte progenitors; and 3) To develop a mouse model of DS-AMKL by creating mice that will conditionally express only the 40-kD isoform of GATA-1 and breeding them to mice with the murine equivalent of DS. Separately, we will also cross these novel GATA1 mutant mice into the BXH-2 strain of mice to identify genes that cooperate with the GATA1 mutations in leukemia. These studies will likely increase our understanding of how GATA1 mutations contribute to the initiation or progression of leukemia in Down syndrome and may also lead to the identification of novel leukemia disease genes on chromosome 21. [unreadable] [unreadable] [unreadable]
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1 |
2007 — 2011 |
Crispino, John D |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Role of Survivin in Development of Megakaryocytes and Erythroid Cells @ Northwestern University
[unreadable] DESCRIPTION (provided by applicant): Although erythroid cells and megakaryocytes derive from a common progenitor and share many essential transcription factors, their terminal maturation follows very different paths: erythroid cells undergo cell cycle exit and enucleation while megakaryocytes continue to progress through the cell cycle, but skip late stages of mitosis to become polyploid cells. In our efforts to identify genes that participate in this process, we discovered that survivin, a member of the inhibitor of apoptosis (IAP) family that also plays an essential role in cytokinesis, is differentially expressed during erythroid versus megakaryocyte development. Erythroid cells express survivin throughout their maturation, up through the terminal orthochromatic stage of differentiation. In contrast, purified murine megakaryocytes express nearly 4-fold lower levels of survivin mRNA compared to erythroid cells and no detectable protein. To investigate whether survivin is involved in the differentiation and/or survival of hematopoietic progenitors, we infected primary mouse bone marrow cells with retroviruses harboring the human survivin cDNA or control retrovirus, and then induced erythroid and megakaryocyte differentiation in both liquid culture and colony-forming assays. These studies revealed that overexpression of survivin antagonized megakaryocyte development, but did not affect the terminal differentiation of red blood cells. In contrast, a 50% reduction in survivin mRNA, caused by a heterozygous loss of survivin, blocked erythroid, but not megakaryocyte, development in vitro. Thus, our preliminary data support a physiologic role for persistent survivin expression in erythroid cells and a significantly reduced level of expression in megakaryocytes. Based on these findings, we hypothesize that persistent survivin expression is required for differentiation and/or survival of erythroid cells, while its reduction is essential for terminal maturation of megakaryocytes. In this application, we propose to investigate how survivin contributes to erythroid cell and megakaryocyte development. Specifically, we plan to 1) Determine the requirement for survivin in red cell and megakaryocyte development by conditional gene targeting in mice, 2) Characterize the mechanism by which survivin participates in erythroid cell differentiation by analyzing the phenotype of cultured erythroid cells with reduced survivin expression and by identifying survivin protein complexes in erythroid cells, and 3) Investigate why persistent survivin expression is inhibitory to megakaryocyte polyploidization and maturation by analysis of transgenic mice that ectopically express survivin in megakaryocytes and erythroid cells. A more detailed assessment of how survivin contributes to hematopoiesis will aid in our understanding of the role of cell cycle regulation and apoptosis in normal blood cell development, and may shed light into the mechanism by which erythroid cells and megakaryocytes arise from a common precursor. [unreadable] [unreadable] [unreadable]
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0.988 |
2008 — 2012 |
Amaral, Luis A. Nunes Carthew, Richard W. Crispino, John D Morimoto, Richard I [⬀] |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Consortium: Northwestern University
We propose to develop a Center for Systems Biology to promote interdisciplinary scientific investigation and education in Chicago. Faculty in the Institute for Genomics and Systems Biology at the University of Chicago will take a leadership role and together with collaborators at other Chicago institutions will create a broad outreach to the community. The Centers scientific program will focus on the robustness of transcriptional networks in physiological, developmental and evolutionary time scales. We propose to go beyond mapping Network topologies to develop dynamical models of the behavior of transcriptional regulatory networks during physiological stress, during cellular and organismal development, and during the evolution of species. These goals will be achieved by bringing together experts in genomics, developmental biology, evolutionary biology, stress and physiology, network modeling, high performance and grid computing, chemistry, and physics. The overarching aim of the Centers research is to uncover the organizational principles that transcriptional regulatory networks share as they respond to physiological, development and evolutionary inputs and pressures. These principles are expected to reveal structure-function relationships in networks that lead to physiological and evolutionary robustness or, its complement, flexibility.
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1 |
2009 — 2010 |
Crispino, John D Galat, Vasil V Soares, Marcelo Bento (co-PI) [⬀] |
RC1Activity Code Description: NIH Challenge Grants in Health and Science Research |
Identification of Altered Molecular Signature of Down Syndrome Ips Cells @ Northwestern University At Chicago
DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (14) Stem Cells and specific Challenge Topic, 14-HL-101: Develop molecular signatures for heart, vascular, lung, and blood diseases by profiling reprogrammed induced pluripotent stem cells derived from affected individuals of defined genotypes. Children with Down syndrome (DS) show a spectrum of clinical abnormalities, including a remarkable incidence of abnormal hematopoietic cell development. As many as 10% of newborns with DS show evidence of transient myeloproliferative disorder (TMD), a disease in which megakaryocyte precursor cells proliferate abnormally. Moreover, infants with TMD show a predisposition to leukemia. The natural history of hematologic abnormalities in children with DS suggests that trisomy 21 directly and functionally contributes to aberrant expansion of hematopoietic cells in the fetal liver during gestation. Consistent with this hypothesis, two studies have recently demonstrated that human fetuses with DS show a significant expansion in megakaryocyte erythroid progenitors and in both erythroid and megakaryocytic colony forming units. In order to better define the molecular differences between euploid and trisomy 21 hematopoietic progenitors, we propose to compare gene expression and methylation profiles of induced pluripotent stem cells (iPSCs) generated from individuals with and without DS. In addition, we will compare the hematopoietic differentiation potential of these two groups of iPSCs as another means to study the effect of DS on blood cell development and disease. Our specific aims are: 1) To generate and characterize trisomic and euploid iPSCs from individuals with and without Down syndrome, 2) To compare the expression of microRNAs and mRNAs in undifferentiated DS and wild-type iPSCs and hematopoietic progenitors derived from these groups of iPSCs, and 3) To characterize the epigenome of DS versus euploid iPSCs. Our long-term goal is to determine which of the microRNAs, mRNAs or methylation differences we detect in trisomy 21 cells contribute to aberrant hematopoiesis in DS. PUBLIC HEALTH RELEVANCE: This research is relevant to multiple human diseases: 1) transient myeloproliferative disease in children with DS, 2) acute leukemia in children with DS, and 3) multiple non-hematopoietic phenotypes that characterize human DS. For complex genetic diseases, such as Down syndrome, powerful new approaches, including the use of human iPSCs, are absolutely critical to improve our understanding of the molecular basis of the disease and the discovery of novel approaches to alleviate symptoms of this disease.
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0.988 |
2012 |
Crispino, John D |
R56Activity Code Description: To provide limited interim research support based on the merit of a pending R01 application while applicant gathers additional data to revise a new or competing renewal application. This grant will underwrite highly meritorious applications that if given the opportunity to revise their application could meet IC recommended standards and would be missed opportunities if not funded. Interim funded ends when the applicant succeeds in obtaining an R01 or other competing award built on the R56 grant. These awards are not renewable. |
Mechanisms of Erythroblast Enucleation @ Northwestern University At Chicago
DESCRIPTION (provided by applicant): Enucleation of mammalian erythroblasts is a process whose mechanism is largely undefined. Until recently, the prevailing models suggested that nuclear extrusion occurs via asymmetric cytokinesis or by a modified apoptotic process. Our recent findings reveal, however, that enucleation is driven in large part by the formation, movement and subsequent coalescence of vacuoles at the junction of the nucleus and the cytoplasm. Here we propose to harness our new insights to improve enucleation of erythroblasts expanded in vitro and to further define the mechanisms that govern terminal differentiation. Our specific aims are to: 1) Determine how vesicle trafficking drives enucleation, 2) Identify novel cellular factors that regulate enucleation, and 3) optimize small molecules that induce enucleation. Our work will enhance our understanding of the final maturation of red cell development and optimization of ex vivo erythrocyte production.
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0.988 |
2013 — 2016 |
Crispino, John D |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Aberrant Megakaryopoiesis in the Myeloproliferative Neoplasms @ Northwestern University At Chicago
DESCRIPTION (provided by applicant): Aberrant regulation of megakaryocyte development is a feature of both essential thrombocythemia (ET) and primary myelofibrosis (PMF). Under normal conditions, committed megakaryocyte progenitors proliferate to a limited extent and then give rise to small numbers of differentiated and polyploid megakaryocytes. However, upon acquisition of mutations in key signaling molecules, such as MPL or JAK2, megakaryocyte progenitors expand and lead to thrombocytosis in ET or myelofibrosis in PMF. The specific molecular changes and mechanisms responsible for the extreme differences in the megakaryocyte phenotype of the two disorders are unknown. In this project, we will identify transcriptional pathways that are dysregulated in PMF megakaryocytes and characterize the causes of aberrant megakaryopoiesis as compared to ET megakaryocytes. We will also determine whether small molecule inducers of megakaryocyte differentiation and polyploidization are effective at restraining the proliferation of aberrant megakaryocytes in MPNs. Finally, we will study the mechanism by which these compounds lead to differentiation and polyploidization of abnormal megakaryocytes. Our overall hypothesis is that megakaryocytes in PMF are abnormal because they aberrantly express myeloid transcription factors and that this program can be reversed with small molecule inducers of megakaryocyte polyploidization and differentiation. This work is innovative in that we are the first to comprehensively describe the differences between PMF and normal megakaryocytes at the molecular level. Moreover, we are using innovative small molecules to advance our understanding of MPNs and to develop new targeted therapies. Our work is significant in that none of the JAK2 inhibitors in clinical trials ameliorate bone marrow myelofibrosis in patients: our research aimed at identifying the root cause of this debilitating condition will aid in development of new therapies.
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0.988 |
2013 — 2017 |
Crispino, John D |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Gata1 Mutation in Defective Erythropoiesis @ Northwestern University At Chicago
DESCRIPTION (provided by applicant): GATA1 is a transcription factor that is required for survival and maturation of erythroid cells. In the absence of GATA1, mouse embryos die from anemia in mid-gestation. In humans, GATA1 mutations are associated with a spectrum of blood disorders, including congenital dyserythropoietic anemia and thrombocytopenia, porphyria, and Diamond-Blackfan Anemia (DBA). In the presence of trisomy 21, GATA1 mutations that delete the N- terminus lead to Down syndrome associated Acute Megakaryoblastic Leukemia (DS-AMKL). We recently demonstrated that a GATA1 mutant, which fails to bind FOG1 and is associated with rare cases of cases of dyserythropoietic anemia, fails to bind chromatin in the same manner as wild-type GATA1. This differential chromatin binding allows GATA1 to promote mast cell formation instead of red cell or megakaryocyte development. In a similar fashion, we have recently discovered that GATA1 molecules that lack the N-terminal activation domain, seen in both DBA and DS-AMKL, also fail to bind chromatin in the same way as full-length GATA1. Of interest, genes that are not properly bound or regulated by GATA1s include critical red cell genes such as Alas2, Slc4a1, and Klf1 (EKLF). In this grant, we will precisely define the requirement for the N- terminus of GATA1 in red cell development. Our aim is to discover how the GATA1 mutations that lead to expression of GATA1s in place of the full-length protein cause defects in the erythroid lineage and congenital anemia, including DBA. Our overarching hypothesis is that the reduced chromatin binding and aberrant gene regulation by GATA1s leads to impaired specification and terminal differentiation of red blood cells. Our aims are to: 1 Correlate chromatin occupancy of GATA1s with gene expression defects in primary GATA1s knock-in erythroid progenitor cells to identify key direct target genes that are dysregulated; 2) Investigate the consequences of the GATA1s mutation on erythroid specification and differentiation; and 3) Determine if loss of the N-terminus reduces the interaction with essential cofactors and in turn affects their chromatin occupancy. The research described in this proposal will greatly expand our insights into how loss of the N-terminus of GATA1 alters erythropoiesis and will benefit patients with congenital anemia and DS-AMKL.
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0.988 |
2017 — 2020 |
Crispino, John D |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Aberrant Megakaryopoiesis in the Myeloproliferative Neoplasms. @ Northwestern University At Chicago
PROJECT SUMMARY Primary myelofibrosis (PMF) is characterized by myeloproliferation, extramedullary hematopoiesis, bone marrow fibrosis, splenomegaly and leukemic progression. Moreover, the bone marrow and spleen of patients are full of atypical megakaryocytes that contribute to fibrosis through the release of cytokines including TGF-?. Our overarching hypothesis is that abnormal megakaryocytes are key drivers of not only bone marrow fibrosis, but also other phenotypes of primary myelofibrosis, and that targeting them will ameliorate the disease. In the first funding period, we identified small molecules that induce maturation and polyploidization of malignant megakaryocytes in mouse models of PMF as well as primary human patient specimens. Based on this NHLBI- funded research, we have opened a Phase 1 trial of one of these megakaryocyte polyploidization agents, Alisertib, in PMF. In this competing renewal, we will probe the molecular nature of the defects in PMF megakaryocytes, and also determine their necessity and sufficiency in the disease. Our preliminary data show that expression of the key transcription factor GATA1 is suppressed in the majority of both human and mouse PMF megakaryocytes and further suggest that this deficiency is due to impaired ribosome function. We also present the surprising result that expression of JAK2V617F selectively in megakaryocytes is sufficient to cause polycythemia in vivo. In Aim 1, we will investigate the link between activated JAK/STAT signaling, GATA1, and ribosome function. In Aim 2 we will study how megakaryocyte expression of JAK2 influences the growth of other cells and also determine whether megakaryocytes are essential for the disease. This work is innovative in that we are the first to reveal that there is defect in ribosomes in a megakaryocytic disorder and that megakaryocyte-selective expression of JAK2V617F leads not only to enhanced megakaryopoiesis, but also to polycythemia in a cell non-autonomous manner. Our research is significant in that it will shed new light on megakaryocyte biology and pathogenesis and may aid in the identification of additional new potential therapies for the MPNs. In addition, our work is also relevant to Diamond Blackfan Anemia, as GATA1 mutations account for a subset of cases and there appears to be a relationship between ribosomal gene mutations and GATA1 translation. Finally, our research will provide additional insights to support the development of agents that selectively target megakaryocytes in this disease.
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0.988 |
2018 — 2020 |
Crispino, John D |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
Cancer Research Career Enhancement and Related Activities @ Northwestern University At Chicago
ABSTRACT ? CANCER RESEARCH CAREER ENHANCEMENT AND RELATED ACTIVITIES The Lurie Cancer Center (LCC) provides a comprehensive training environment to enhance the career development of cancer researchers and caregivers at all levels. Education and training at the LCC is led by Dr. John Crispino, Associate Director for Education and Training since 2012, with support of several faculty and LCC staff. The combination of substantial NIH training grant funding and dedicated philanthropic support enables numerous training opportunities for students, research fellows, clinical fellows, oncology nurses, and junior faculty. These include numerous seminar series, symposia, retreats, intramural grants, and travel awards. The LCC manages five NCI T32 grants, and trainees are further supported by four other cancer relevant T32 grants and two K12 grants. New to this cycle are a formal mentorship program for clinical trainees and the Translational Bridge Initiative, which provides combined laboratory and clinical mentor oversight for selected post-doctoral fellows. In addition, there are LCC-sponsored education opportunities for health care professionals and oncologists in the Chicago area, nationally and internationally. Over the next funding period the LCC will continue to expand the ongoing activities, optimize training for precision medicine and other emerging fields and intensify efforts to increase the diversity of our trainees.
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0.988 |
2019 — 2021 |
Crispino, John D |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Identifying the Pathways That Drive Progression of the Mpns to Aml @ Northwestern University At Chicago
PROJECT SUMMARY The myeloproliferative neoplasms (MPNs), which include polycythemia vera, essential thrombocythemia, and primary myelofibrosis, are closely related clonal hematopoietic disorders that are characterized by extramedullary hematopoiesis, bleeding disorders, a shortened lifespan, and a propensity to evolve to AML. Currently there is no way to predict which patients will develop AML, and little is known about the genetic events that are associated with progression. The identification of drivers of leukemic transformation will improve our understanding of the disease and provide novel targets for therapeutic intervention. To define the pathways that drive AML progression, we performed a focused CRISPR/Cas9 screen to identify genes whose editing resulted in hematopoietic progenitor cell self-renewal of Jak2V617F cells but not wild-type progenitors. We identified STK11 and RPS6KA2 as two genes whose editing cooperates with the JAK2 mutant to promote transformation in vitro. Importantly we also found that STK11 and RPS6KA2 are downregulated and mutated in post-MPN AML, respectively, but not in chronic phase MPN. These results are highly innovative, provide significant insights into disease progression, and reveal two new pathways to development of AML. We hypothesize that alterations in STK11 induce AML by suppressing the activity of its substrates, including AMPK, and consequently altering cellular metabolism and protein translation, leading to increased expression of oncogenic proteins. Similarly, we hypothesize that genetic alterations in RPS6KA2 cause AML by impairing STK11 function and/or enhancing mTORC1 signaling and oncogenic protein translation. We propose to delve into the contributions of STK11 and RPS6KA2 to MPN progression by the following aims: 1) Investigate the mechanisms by which loss of STK11 induces progression of JAK2V617F mutant MPN to AML; and 2) Elucidate the contributions of alterations in RPS6KA2 to the progression of MPN to AML. Together these studies will yield important new insights into the genetic basis and mechanisms by which AML arises from the MPNs.
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0.988 |
2020 |
Crispino, John D |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Aberrant Megakaryopoiesis in the Myleoproliferative Neoplasms @ St. Jude Children's Research Hospital
PROJECT SUMMARY Primary myelofibrosis (PMF) is characterized by myeloproliferation, extramedullary hematopoiesis, bone marrow fibrosis, splenomegaly and leukemic progression. Moreover, the bone marrow and spleen of patients are full of atypical megakaryocytes that contribute to fibrosis through the release of cytokines including TGF-?. Our overarching hypothesis is that abnormal megakaryocytes are key drivers of not only bone marrow fibrosis, but also other phenotypes of primary myelofibrosis, and that targeting them will ameliorate the disease. In the first funding period, we identified small molecules that induce maturation and polyploidization of malignant megakaryocytes in mouse models of PMF as well as primary human patient specimens. Based on this NHLBI- funded research, we have opened a Phase 1 trial of one of these megakaryocyte polyploidization agents, Alisertib, in PMF. In this competing renewal, we will probe the molecular nature of the defects in PMF megakaryocytes, and also determine their necessity and sufficiency in the disease. Our preliminary data show that expression of the key transcription factor GATA1 is suppressed in the majority of both human and mouse PMF megakaryocytes and further suggest that this deficiency is due to impaired ribosome function. We also present the surprising result that expression of JAK2V617F selectively in megakaryocytes is sufficient to cause polycythemia in vivo. In Aim 1, we will investigate the link between activated JAK/STAT signaling, GATA1, and ribosome function. In Aim 2 we will study how megakaryocyte expression of JAK2 influences the growth of other cells and also determine whether megakaryocytes are essential for the disease. This work is innovative in that we are the first to reveal that there is defect in ribosomes in a megakaryocytic disorder and that megakaryocyte-selective expression of JAK2V617F leads not only to enhanced megakaryopoiesis, but also to polycythemia in a cell non-autonomous manner. Our research is significant in that it will shed new light on megakaryocyte biology and pathogenesis and may aid in the identification of additional new potential therapies for the MPNs. In addition, our work is also relevant to Diamond Blackfan Anemia, as GATA1 mutations account for a subset of cases and there appears to be a relationship between ribosomal gene mutations and GATA1 translation. Finally, our research will provide additional insights to support the development of agents that selectively target megakaryocytes in this disease.
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0.909 |