RESUMO
BACKGROUND: Patients with JAK2V617F-positive myeloproliferative neoplasms (MPNs) and clonal hematopoiesis of indeterminate potential face a significantly elevated risk of cardiovascular diseases. Endothelial cells carrying the JAK2V617F mutation have been detected in many patients with MPN. In this study, we investigated the molecular basis for the high incidence of cardiovascular complications in patients with MPN. METHODS: We investigated the impact of endothelial JAK2V617F mutation on cardiovascular disease development using both transgenic murine models and MPN patient-derived induced pluripotent stem cell lines. RESULTS: Our investigations revealed that JAK2V617F mutant endothelial cells promote cardiovascular diseases under stress, which is associated with endothelial-to-mesenchymal transition and endothelial dysfunction. Importantly, we discovered that inhibiting the endothelial TPO (thrombopoietin) receptor MPL (myeloproliferative leukemia virus oncogene) suppressed JAK2V617F-induced endothelial-to-mesenchymal transition and prevented cardiovascular dysfunction caused by mutant endothelial cells. Notably, the endothelial MPL receptor is not essential for the normal physiological regulation of blood cell counts and cardiac function. CONCLUSIONS: JAK2V617F mutant endothelial cells play a critical role in the development of cardiovascular diseases in JAK2V617F-positive MPNs, and endothelial MPL could be a promising therapeutic target for preventing or ameliorating cardiovascular complications in these patients.
Assuntos
Doenças Cardiovasculares , Células Endoteliais , Células-Tronco Pluripotentes Induzidas , Janus Quinase 2 , Mutação , Transtornos Mieloproliferativos , Receptores de Trombopoetina , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Receptores de Trombopoetina/genética , Animais , Humanos , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/enzimologia , Transtornos Mieloproliferativos/complicações , Transtornos Mieloproliferativos/metabolismo , Células Endoteliais/enzimologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/enzimologia , Doenças Cardiovasculares/etiologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/enzimologia , Camundongos Transgênicos , Transdução de Sinais , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , CamundongosRESUMO
Megakaryocytes (MKs) is an important component of the hematopoietic niche. Abnormal MK hyperplasia is a hallmark feature of myeloproliferative neoplasms (MPNs). The JAK2V617F mutation is present in hematopoietic cells in a majority of patients with MPNs. Using a murine model of MPN in which the human JAK2V617F gene is expressed in the MK lineage, we show that the JAK2V617F-bearing MKs promote hematopoietic stem cell (HSC) aging, manifesting as myeloid-skewed hematopoiesis with an expansion of CD41+ HSCs, a reduced engraftment and self-renewal capacity, and a reduced differentiation capacity. HSCs from 2-year-old mice with JAK2V617F-bearing MKs were more proliferative and less quiescent than HSCs from age-matched control mice. Examination of the marrow hematopoietic niche reveals that the JAK2V617F-bearing MKs not only have decreased direct interactions with hematopoietic stem/progenitor cells during aging but also suppress the vascular niche function during aging. Unbiased RNA expression profiling reveals that HSC aging has a profound effect on MK transcriptomic profiles, while targeted cytokine array shows that the JAK2V617F-bearing MKs can alter the hematopoietic niche through increased levels of pro-inflammatory and anti-angiogenic factors. Therefore, as a hematopoietic niche cell, MKs represent an important connection between the extrinsic and intrinsic mechanisms for HSC aging.
Assuntos
Transtornos Mieloproliferativos , Neoplasias , Envelhecimento/genética , Animais , Modelos Animais de Doenças , Humanos , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Megacariócitos/metabolismo , Camundongos , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/metabolismoRESUMO
The chronic myeloproliferative neoplasms (MPNs) are clonal stem cell disorders. The hematopoietic stem/progenitor cell (HSPC) compartment in patients with MPNs is heterogeneous with the presence of both wild-type and JAK2V617F mutant cells. Mechanisms responsible for mutant stem cell expansion in MPNs are not fully understood. Vascular endothelial cells (ECs) are an essential component of the hematopoietic microenvironment. ECs carrying the JAK2V617F mutation can be detected in patients with MPNs. Utilizing an ex vivo EC-HSPC co-culture system with mixed wild-type and JAK2V617F mutant ECs, we show that even small numbers of JAK2V617F mutant ECs can promote the expansion of JAK2V617F mutant HSPCs in preference to wild-type HSPCs during irradiation or cytotoxic chemotherapy, the two treatments commonly used in the conditioning regimen for stem cell transplantation, the only curative treatment for patients with MPNs. Mechanistically, we found that both cell-cell interactions and secreted factors are important for JAK2V617F mutant EC-mediated neoplastic hematopoiesis. Further understanding of how the JAK2V617F mutation alters vascular niche function will help identify new strategies to not only control neoplastic cell expansion but also prevent disease relapse in patients with MPNs.
Assuntos
Células Endoteliais/enzimologia , Neoplasias Hematológicas , Hematopoese , Células-Tronco Hematopoéticas/enzimologia , Janus Quinase 2 , Mutação de Sentido Incorreto , Transtornos Mieloproliferativos , Células-Tronco Neoplásicas/enzimologia , Microambiente Tumoral , Substituição de Aminoácidos , Animais , Neoplasias Hematológicas/enzimologia , Neoplasias Hematológicas/genética , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Camundongos , Camundongos Transgênicos , Transtornos Mieloproliferativos/enzimologia , Transtornos Mieloproliferativos/genéticaRESUMO
Hematopoietic stem cells (HSCs) rely on instructive cues from the marrow microenvironment for their maintenance and function. Accumulating evidence indicates that the survival and proliferation of hematopoietic neoplasms are dependent not only on cell-intrinsic, genetic mutations, and other molecular alterations present within neoplastic stem cells, but also on the ability of the surrounding microenvironmental cells to nurture and promote the malignancy. It is anticipated that a better understanding of the molecular and cellular events responsible for these microenvironmental features of neoplastic hematopoiesis will lead to improved treatment for patients. This review will focus on the myeloproliferative neoplasms (MPNs), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), in which an acquired signaling kinase mutation (JAK2V617F) plays a central, pathogenetic role in 50-100% of patients with these disorders. Evidence is presented that the development of an MPN requires both an abnormal, mutation-bearing (i.e., neoplastic) HSC and an abnormal, mutation-bearing microenvironment.
Assuntos
Células-Tronco Hematopoéticas/citologia , Transtornos Mieloproliferativos/patologia , Neoplasias/patologia , Nicho de Células-Tronco , Microambiente Tumoral , Humanos , Janus Quinase 2/genética , Mutação , Transtornos Mieloproliferativos/genética , Neoplasias/genéticaRESUMO
The myeloproliferative neoplasms (MPNs) are stem cell disorders characterized by hematopoietic stem/progenitor cell (HSPC) expansion and overproduction of mature blood cells. The acquired kinase mutation JAK2V617F plays a central role in these disorders. The mechanisms responsible for HSPC expansion in MPNs are not fully understood, limiting the effectiveness of current treatments. One hallmark feature of the marrow in patients with MPNs is megakaryocyte (MK) hyperplasia. Previously, we reported that JAK2V617F-bearing MKs cause a murine myeloproliferative syndrome with HSPC expansion. Here we show that JAK2V617F MKs promote MPN stem cell function by inducing HSPC quiescence with increased repopulating capacity. In addition, we demonstrate that thrombopoietin and its receptor MPL are critical for the JAK2V617F-bearing MK-induced myeloproliferation, both by directly affecting the quantity and quality of MKs and by altering the MK-endothelial interaction and vascular niche function. Therefore, targeting HSPC niche-forming MKs and/or their interactions within the vascular niche could provide novel, more effective therapeutic strategies in patients with MPNs. Stem Cells 2018;36:1676-1684.
Assuntos
Células-Tronco Hematopoéticas/enzimologia , Janus Quinase 2/metabolismo , Megacariócitos/metabolismo , Transtornos Mieloproliferativos/metabolismo , Receptores de Trombopoetina/metabolismo , Trombopoetina/metabolismo , Animais , Proliferação de Células/fisiologia , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Janus Quinase 2/genética , Megacariócitos/enzimologia , Megacariócitos/patologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Mutação , Transtornos Mieloproliferativos/enzimologia , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/patologia , Transdução de Sinais , Trombopoetina/genéticaRESUMO
Myeloproliferative neoplasms are clonal stem cell disorders characterized by hematopoietic stem/progenitor cell expansion. The acquired kinase mutation JAK2V617F plays a central role in these disorders. Abnormalities of the marrow microenvironment are beginning to be recognized as an important factor in the development of myeloproliferative neoplasms. Endothelial cells are an essential component of the hematopoietic vascular niche. Endothelial cells carrying the JAK2V617F mutation can be detected in patients with myeloproliferative neoplasms, suggesting that the mutant vascular niche is involved in the pathogenesis of these disorders. Here, using a transgenic mouse expressing JAK2V617F specifically in all hematopoietic cells (including hematopoietic stem/progenitor cells) and endothelial cells, we show that the JAK2V617F-mutant hematopoietic stem/progenitor cells are relatively protected by the JAK2V617F-bearing vascular niche from an otherwise lethal dose of irradiation during conditioning for stem cell transplantation. Gene expression analysis revealed that chemokine (C-X-C motif) ligand 12, epidermal growth factor, and pleiotrophin are up-regulated in irradiated JAK2V617F-bearing endothelial cells compared to wild-type cells. Our findings suggest that the mutant vascular niche may contribute to the high incidence of disease relapse in patients with myeloproliferative neoplasms following allogeneic stem cell transplantation, the only curative treatment for these disorders.
Assuntos
Substituição de Aminoácidos , Neoplasias Hematológicas/etiologia , Neoplasias Hematológicas/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Janus Quinase 2/genética , Mutação , Lesões por Radiação/complicações , Animais , Apoptose/genética , Apoptose/efeitos da radiação , Relação Dose-Resposta à Radiação , Células Endoteliais/metabolismo , Expressão Gênica , Neoplasias Hematológicas/patologia , Hematopoese/genética , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/efeitos da radiação , Camundongos , Camundongos Transgênicos , Tolerância a Radiação/genética , Regeneração , Microambiente Tumoral/genética , Microambiente Tumoral/efeitos da radiaçãoRESUMO
The myeloproliferative neoplasms (MPNs) are characterized by hematopoietic stem/progenitor cell (HSPC) expansion and overproduction of blood cells. The acquired mutation JAK2V617F plays a central role in these disorders. Mechanisms responsible for MPN HSPC expansion is not fully understood, limiting the effectiveness of current treatments. Endothelial cells (ECs) carrying the JAK2V617F mutation can be detected in patients with MPNs, suggesting that ECs are involved in the pathogenesis of MPNs. Here we report that JAK2V617F-bearing primary murine ECs have increased cell proliferation and angiogenesis in vitro compared to JAK2WT ECs. While there was no difference between JAK2V617F and JAK2WT HSPC proliferation when co-cultured with JAK2WT EC, the JAK2V617F HSPC displayed a relative growth advantage over the JAK2WT HSPC when co-cultured on JAK2V617F EC. In addition, the thrombopoietin (TPO) receptor MPL is up regulated in JAK2V617F ECs and contributes to the maintenance/expansion of the JAK2V617F clone over JAK2WT clone in vitro. Considering that ECs are an essential component of the hematopoietic niche and most HSPCs reside in the perivascular niche, our studies suggest that the JAK2V617F-bearing ECs form an important component of the MPN vascular niche and contribute to mutant stem/progenitor cell expansion, likely through a critical role of the TPO/MPL signaling axis.
Assuntos
Proliferação de Células/genética , Janus Quinase 2/genética , Transtornos Mieloproliferativos/genética , Receptores de Trombopoetina/fisiologia , Animais , Técnicas de Cocultura , Células Endoteliais/patologia , Humanos , Camundongos , Mutação de Sentido Incorreto , Transtornos Mieloproliferativos/patologia , Neoplasias/genética , Neovascularização Patológica , Receptores de Trombopoetina/metabolismo , Nicho de Células-TroncoRESUMO
JAK2(V617F) mutation can be detected in the majority of myeloproliferative neoplasm (MPN) patients. The JAK2 inhibitor Ruxolitinib is the first FDA-approved treatment for MPNs. However, its use is limited by various dose related toxicities. Here, we studied the metabolic state and glutamine metabolism of BaF3-hEPOR-JAK2V617F and BaF3-hEPOR-JAK2WT cells. We found that the JAK2(V617F)-mutant cells were associated with increased oxygen consumption rate and extracellular acidification rate than the JAK2(WT) cells and there was an increased glutamine metabolism in JAK2(V617F)-mutant cells compared to wild-type cells. Glutaminase (GLS), the key enzyme in glutamine metabolism, was upregulated in the JAK2(V617F)-mutant BaF3 cells compared to the JAK2(WT) BaF3 cells. In MPN patient peripheral blood CD34+ cells, GLS expression was increased in JAK2(V617F)-mutant progenitor cells compared to JAK2 wild-type progenitor cells from the same patients and GLS levels were increased at the time of disease progression compared to at earlier time points. Moreover, GLS inhibitor increased the growth inhibitory effect of Ruxolitinib in both JAK2(V617F)-mutant cell lines and peripheral blood CD34+ cells from MPN patients. Therefore, GLS inhibitor should be further explored to enhance the therapeutic effectiveness of JAK2 inhibitor and allow the administration of lower doses of the drug to avoid its toxicity.
Assuntos
Glutamina/metabolismo , Janus Quinase 2/metabolismo , Transtornos Mieloproliferativos/metabolismo , Linhagem Celular Tumoral , Humanos , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/genética , Mutação , Nitrilas , Pirazóis/farmacologia , Pirimidinas , Regulação para CimaRESUMO
Thrombopoietin (TPO) and its receptor MPL play crucial roles in hematopoietic stem cell (HSC) function and platelet production. However, the precise effects of TPO/MPL signaling on HSC regulation in different hematopoietic niches remain unclear. Here, we investigated the effects of TPO/MPL ablation on marrow and splenic hematopoiesis in TPO-/- and MPL-/- mice during aging. Despite severe thrombocytopenia, TPO-/- and MPL-/- mice did not develop marrow failure during a 2-year follow-up. Marrow and splenic HSCs exhibited different responses to TPO/MPL ablation and exogenous TPO treatment. Splenic niche cells compensated for marrow HSC loss in TPO-/- and MPL-/- mice by upregulating CXCL12 levels. These findings provide new insights into the complex regulation of HSCs by TPO/MPL and reveal a previously unknown link between TPO and CXCL12, two key growth factors for HSC maintenance. Understanding the distinct regulatory mechanisms between marrow and spleen hematopoiesis will help to develop novel therapeutic approaches for hematopoietic disorders.
Assuntos
Medula Óssea , Baço , Camundongos , Animais , Medula Óssea/metabolismo , Baço/metabolismo , Trombopoetina/farmacologia , Receptores de Trombopoetina/genética , Receptores de Trombopoetina/metabolismo , Células-Tronco Hematopoéticas/metabolismoRESUMO
This review critically analyzes the incidence of trastuzumab-induced left ventricular systolic dysfunction and congestive heart failure (CHF), distinguishing between cases with and without prior anthracycline exposure. It highlights the fact that the elevated risk of trastuzumab-induced cardiotoxicity is closely associated with prior anthracycline exposure. In the absence of prior anthracycline exposure, the incidence rates of trastuzumab-induced cardiotoxicity, particularly CHF (ranging from 0% to 0.5%), are largely comparable with those reported in the general population, especially when reversibility is taken into account. Current cardiac surveillance recommendations during trastuzumab treatment have not yet adapted to the increasing adoption of nonanthracycline treatment strategies and the associated low risk of cardiotoxicity. We propose a refined monitoring protocol to reduce the frequency of cardiac evaluations for low-risk to moderate-risk patients, especially those receiving nonanthracycline treatments. By focusing on patients at high risk or those with prior anthracycline exposure, this strategy seeks to optimize the cost-effectiveness of cardiac care in oncology.
Assuntos
Cardiotoxicidade , Trastuzumab , Humanos , Trastuzumab/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Antraciclinas/efeitos adversos , Insuficiência Cardíaca/induzido quimicamenteRESUMO
The chronic myeloproliferative neoplasms (MPN), including polycythaemia vera (PV), essential thrombocythaemia (ET) and primary myelofibrosis (PMF), are clonal stem cell disorders characterized by dysregulated haematopoietic stem cell expansion and production of red cells, white cells and platelets alone or in combination. An acquired mutation JAK2(V617F) can be found in all three disorders and shows many of the phenotypic abnormalities of the diseases in murine models. The disease phenotype is also influenced by other unknown genetic or epigenetic factors. MicroRNAs (miRNA) are 18-24 nucleotide single-stranded non-protein-coding RNAs that function primarily as gene repressors by binding to their target messenger RNAs. There is growing evidence that miRNAs regulate haematopoiesis in both haematopoietic stem cells and committed progenitor cells. Here, we review the field of miRNA biology and its regulatory roles in normal haematopoiesis with an emphasis on miRNA deregulations in MPNs. Continued research into how miRNAs impact JAK2(V617F) clonal expansion, differential haematopoiesis among different MPNs, disease progression and leukaemia transformation will lead to a better understanding of the development of these disorders, their clinical manifestations, and their treatment.
Assuntos
MicroRNAs/genética , Transtornos Mieloproliferativos/genética , Regulação Neoplásica da Expressão Gênica , Hematopoese/genética , Humanos , MicroRNAs/metabolismo , MicroRNAs/uso terapêutico , Transtornos Mieloproliferativos/metabolismo , Transtornos Mieloproliferativos/terapiaRESUMO
Polycythemia vera (PV) and essential thrombocythemia (ET) are the two most common myeloproliferative neoplasms. The same JAK2(V617F) mutation can be found in both disorders and is able to recapitulate many of the phenotypic abnormalities of these diseases in the murine models. The disease phenotype is also influenced by other unknown genetic or epigenetic factors. MicroRNAs (miRNA) are 18-24 nucleotides single-stranded non-protein-coding RNAs that function primarily as gene repressors by binding to their target messenger RNAs. We performed miRNA expression profiling by oligonucleotide microarray analysis in purified peripheral blood CD34+ cells from eight JAK2(V617F)-positive PV patients and six healthy donors. A quantitative reverse-transcription polymerase chain reaction assay was used to verify differential miRNA expression. Since erythrocytosis is the only feature that distinguishes PV from ET, we also compared specific miRNA expression in the nucleated erythroid cells directly descended from the early erythroid progenitor cells of PV and ET patients. Our data indicate that significant miRNA deregulation occurs in PV CD34+ cells and confirm a genetic basis for the gender-specific differences that characterize PV with respect to miRNA. The results of our study also suggest that deregulated miRNAs may represent an important mechanism by which the PV erythrocytosis and ET thrombocytosis phenotypes are determined.
Assuntos
Regulação da Expressão Gênica , MicroRNAs/genética , Policitemia Vera/genética , Trombocitemia Essencial/genética , Adulto , Idoso , Antígenos CD34 , Estudos de Casos e Controles , Eritropoese/genética , Feminino , Perfilação da Expressão Gênica , Células-Tronco Hematopoéticas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Fatores SexuaisRESUMO
Thrombopoietin (TPO) and its receptor MPL play crucial roles in hematopoietic stem cell (HSC) function and platelet production. However, the precise effects of TPO/MPL signaling on HSC regulation in different hematopoietic niches remain unclear. Here, we investigated the effects of TPO/MPL ablation on marrow and splenic hematopoiesis in TPO-/- and MPL-/- mice during aging. Despite severe thrombocytopenia, TPO-/- and MPL-/- mice did not develop marrow failure during a 2-year follow-up. Marrow and splenic HSCs exhibited different responses to TPO/MPL ablation and exogenous TPO treatment. Splenic niche cells compensated for marrow HSC loss in TPO-/- and MPL-/- mice by upregulating CXCL12 levels. These findings provide new insights into the complex regulation of HSCs by TPO/MPL and reveal a previously unknown link between TPO and CXCL12, two key growth factors for HSC maintenance. Understanding the distinct regulatory mechanisms between marrow and spleen hematopoiesis will help develop novel therapeutic approaches for hematopoietic disorders.
RESUMO
Patients with JAK2V617F-positive myeloproliferative neoplasms (MPNs) and clonal hematopoiesis of indeterminate potential (CHIP) are at a significantly higher risk of cardiovascular diseases (CVDs). Endothelial cells (ECs) carrying the JAK2V617F mutation can be detected in many MPN patients. Here, we investigated the impact of endothelial JAK2V617F mutation on CVD development using both transgenic murine models and human induced pluripotent stem cell lines. Our findings revealed that JAK2V617F mutant ECs promote CVDs by impairing endothelial function and undergoing endothelial-to-mesenchymal transition (EndMT). Importantly, we found that inhibiting the endothelial thrombopoietin receptor MPL suppressed JAK2V617F-induced EndMT and prevented cardiovascular dysfunction caused by mutant ECs. These findings propose that targeting the endothelial MPL receptor could be a promising therapeutic approach to manage CVD complications in patients with JAK2V617F-positive MPNs and CHIP. Further investigations into the impact of other CHIP-associated mutations on endothelial dysfunction are needed to improve risk stratification for individuals with CHIP.
RESUMO
Megakaryocytes (MKs) are important components of the hematopoietic niche. Compared to the non-hematopoietic niche cells, MKs serving as part of the hematopoietic niche provides a mechanism for feedback regulation of hematopoietic stem cells (HSCs), in which HSC progeny (MKs) can modulate HSC adaptation to hematopoietic demands during both steady-state and stress hematopoiesis. MKs are often located adjacent to marrow sinusoids. Considering that most HSCs reside close to a marrow vascular sinusoid, as do MKs, the interactions between MKs and vascular endothelial cells are positioned to play important roles in modulating HSC function, and by extrapolation, might be dysregulated in various disease states. In this review, we discuss the interactions between MKs and the vascular niche in both normal and neoplastic hematopoiesis.
RESUMO
Human induced pluripotent stem (iPS) cells derived from somatic cells hold promise to develop novel patient-specific cell therapies and research models for inherited and acquired diseases. We and others previously reprogrammed human adherent cells, such as postnatal fibroblasts to iPS cells, which resemble adherent embryonic stem cells. Here we report derivation of iPS cells from postnatal human blood cells and the potential of these pluripotent cells for disease modeling. Multiple human iPS cell lines were generated from previously frozen cord blood or adult CD34(+) cells of healthy donors, and could be redirected to hematopoietic differentiation. Multiple iPS cell lines were also generated from peripheral blood CD34(+) cells of 2 patients with myeloproliferative disorders (MPDs) who acquired the JAK2-V617F somatic mutation in their blood cells. The MPD-derived iPS cells containing the mutation appeared normal in phenotypes, karyotype, and pluripotency. After directed hematopoietic differentiation, the MPD-iPS cell-derived hematopoietic progenitor (CD34(+)CD45(+)) cells showed the increased erythropoiesis and gene expression of specific genes, recapitulating features of the primary CD34(+) cells of the corresponding patient from whom the iPS cells were derived. These iPS cells provide a renewable cell source and a prospective hematopoiesis model for investigating MPD pathogenesis.
Assuntos
Células-Tronco Hematopoéticas/citologia , Células-Tronco Pluripotentes Induzidas/citologia , Transtornos Mieloproliferativos/sangue , Adulto , Animais , Antígenos CD34/metabolismo , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Diferenciação Celular , Linhagem Celular , Linhagem Celular Tumoral , Eritropoese , Sangue Fetal/citologia , Sangue Fetal/metabolismo , Perfilação da Expressão Gênica , Hematopoese , Células-Tronco Hematopoéticas/metabolismo , Humanos , Imuno-Histoquímica , Células-Tronco Pluripotentes Induzidas/metabolismo , Janus Quinase 2/genética , Antígenos Comuns de Leucócito/metabolismo , Camundongos , Mutação , Transtornos Mieloproliferativos/genética , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
The myeloproliferative neoplasms (MPNs) are characterized by an expansion of the neoplastic hematopoietic stem/progenitor cells (HSPC) and an increased risk of cardiovascular complications. The acquired kinase mutation JAK2V617F is present in hematopoietic cells in a majority of patients with MPNs. Vascular endothelial cells (ECs) carrying the JAK2V617F mutation can also be detected in patients with MPNs. In this study, we show that a murine model with both JAK2V617F-bearing hematopoietic cells and JAK2V617F-bearing vascular ECs recapitulated all the key features of the human MPN disease, which include disease transformation from essential thrombocythemia to myelofibrosis, extramedullary splenic hematopoiesis, and spontaneous cardiovascular complications. We also found that, during aging and MPN disease progression, there was a loss of both HSPC number and HSPC function in the marrow while the neoplastic hematopoiesis was relatively maintained in the spleen, mimicking the advanced phases of human MPN disease. Different vascular niche of the marrow and spleen could contribute to the different JAK2V617F mutant stem cell functions we have observed in this JAK2V617F-positive murine model. These results indicate that the spleen is functionally important for the JAK2V617F mutant neoplastic hematopoiesis during aging and MPN disease progression. Compared to other MPN murine models reported so far, our studies demonstrate that JAK2V617F-bearing vascular ECs play an important role in both the hematologic and cardiovascular abnormalities of MPN.
RESUMO
Disease relapse after allogeneic stem cell transplantation is a major cause of treatment-related morbidity and mortality in patients with myeloproliferative neoplasms (MPNs). The cellular and molecular mechanisms for MPN relapse are not well understood. Here, we established a murine model of MPN relapse, in which ~ 60% of the MPN recipient mice develop disease relapse after receiving stem cell transplantation with wild-type marrow donor. Using this model, we find that impaired wild-type cell function is associated with MPN disease relapse. We also show that competition between wild-type and JAK2V617F mutant cells can modulate the immune cell composition and PD-L1 expression induced by the JAK2V617F oncogene. These results suggest that cell competition between wild-type donor cells and JAK2V617F mutant recipient cells can prevent MPN disease relapse after stem cell transplantation.
RESUMO
BACKGROUND: Plasma exchange, the standard treatment for thrombotic thrombocytopenic purpura (TTP), has significantly decreased disease mortality. However, TTP recurs in 20% to 50% of patients who survive the initial episode. We aimed to describe the clinical spectrum of TTP, to determine the valid endpoint for plasma exchange cessation, and to explore the risk factors for disease relapse. STUDY DESIGN AND METHODS: Using the ICD-9 diagnosis code, we identified patients treated for TTP at the Johns Hopkins Hospital between 1992 and 2008. Complete demographic, clinical, laboratory, treatment, and outcome data were collected from the medical records. RESULTS: A total of 72 patients were treated for 134 episodes of TTP at the Johns Hopkins Hospital during the study period. With standardized combined immunosuppression and plasma exchange treatment, the all-cause mortality rate was 4%. Lactate dehydrogenase (LDH) normalization lagged behind platelet (PLT) recovery by an average of 9 days and did not predict response. Relapse occurred in 36% of patients during a median follow-up of 30 months with most (76%) occurring in the first 24 months. African American ethnicity was associated with increased risk of relapse (odds ratio = 4.8, p = 0.03). CONCLUSIONS: Excellent outcomes in patients with TTP are achievable with multimodality therapy. LDH normalization lags behind PLT recovery and might not be an informative endpoint for plasma exchange cessation. Prospective studies are warranted to confirm the influence of race on relapse and identify additional risk factors for adverse outcomes that could be targeted to improve therapeutic outcomes for patients with TTP.