scholarly journals Chronic Lymphocytic Leukemia and Myelofibrosis

2018 ◽  
Vol 2018 ◽  
pp. 1-5 ◽  
Author(s):  
Fares Darawshy ◽  
Arieh Ben-Yehuda ◽  
Karine Atlan ◽  
Deborah Rund
Keyword(s):  
Bone Marrow ◽  
Clinical Course ◽  
Case Reports ◽  
Primary Myelofibrosis ◽  
Lymphocytic Leukemia ◽  
Molecular Characteristics ◽  
Review Of Literature ◽  
V617f Mutation ◽  
Unusual Situation

Background. Chronic lymphocytic lymphoma (CLL) can be associated with several malignancies, but rarely with myelofibrosis. Only isolated case reports in the literature described the association between CLL and primary myelofibrosis (PMF) in the same patient. Objectives. We describe a case of CLL characterized by the development of PMF and a review of literature. Methods. We describe an 86-year-old female diagnosed as having CLL and followed by the development of splenomegaly and progressively rising LDH levels 27 months later. A bone marrow biopsy was consistent with the diagnosis of PMF, with positive JAK-2 V617F mutation. We also review the clinical and molecular characteristics of patients with CLL and PMF. Results. Patients with CLL and PMF are usually older. A lead diagnosis of CLL harbored by PMF is the most common clinical course, although concomitant diseases may occur in 31.7% of patients. JAK-2 V617F mutation can be found in 48.7% of patients. Conclusion. This case reported here constitutes an unusual situation of CLL characterized by the development of PMF. Etiologic and pathogenic associations—the role of t (1; 6) and JAK-2 V617F mutation—are discussed.

scholarly journals A Case of Lymphocytic Leukemia in a Bearded Dragon (Pogona vitticeps) and a Review of Literature

2019 ◽  
Vol 69 (3) ◽  
pp. 360-368
Author(s):  
Alessandra Gavazza ◽  
Livio Galosi ◽  
Veronica Croce ◽  
Amerio Croce ◽  
Carla Genovese ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Lymphocytic Leukemia ◽  
Lymphoid Cells ◽  
Immunocytochemical Staining ◽  
Review Of Literature ◽  
Blood Smears ◽  
Bearded Dragon ◽  
Pogona Vitticeps ◽  
Lymphoid Infiltration ◽  
Lymphoblastic Cells

Abstract The present paper reports the case of a 3 years old, female Bearded Dragon (Pogona vitticeps) presenting lethargy, anorexia, weight loss, and anemia and marked leukocytosis at CBC. The majority of leukocytes were lymphocytic/lymphoblastic cells (97%). Immunocytochemical staining of blood smears marked for CD3 (neg) and CD79a (pos) suggested immunophenotype B. The patient died after one month from diagnosis. Histology evidenced lymphoid infiltration in the heart, spleen, liver, kidneys and gut. In addition, in the bone marrow a massive infiltration of lymphoid cells confirmed the diagnosis of leukemia. Immunohistochemistry confirmed the CD79a positivity of a large part of infiltrating lymphoid cells indicating a B cells immunophenotype of the neoplastic population. The presence of lymphocytosis and multiorgan infiltration supported the diagnosis of lymphocytic leukemia. Finally, a revision of the literature has also been made.

Isolated testicular relapse in acute lymphocytic leukemia of childhood: categories and influence on survival.

1984 ◽  
Vol 2 (8) ◽  
pp. 924-929 ◽  
Author(s):  
W P Bowman ◽  
R J Aur ◽  
H O Hustu ◽  
G Rivera
Keyword(s):  
Bone Marrow ◽  
Complete Remission ◽  
Acute Lymphocytic Leukemia ◽  
Clinical Course ◽  
Late Recurrence ◽  
Lymphocytic Leukemia ◽  
Drug Resistant ◽  
Prognostic Features ◽  
Resistant Disease ◽  
Testicular Disease

Isolated testicular relapse complicating first hematologic remission was identified in 31 of 521 boys with acute lymphocytic leukemia (ALL). Three categories of involvement were apparent and could be related to presenting clinical features, duration of initial complete remission, and length of hematologic remission. Among 12 patients with early testicular relapse, most had unfavorable prognostic features when ALL was first diagnosed. All but two of these children experienced marrow recurrence within seven months of testicular relapse. In contrast, the 12 patients who developed testicular disease late in their clinical course have responded much better to further therapy; ten remain in bone-marrow remission for a median of four years beyond testicular relapse. Similarly, five of the seven patients with subclinical testicular leukemia, found at elective biopsy, continue in marrow remission for prolonged periods. Early testicular recurrence is a sign of drug-resistant disease; late recurrence after elective cessation of therapy may represent residual, incompletely treated but still responsive leukemia.

scholarly journals Role of neoplastic monocyte-derived fibrocytes in primary myelofibrosis

2016 ◽  
Vol 213 (9) ◽  
pp. 1723-1740 ◽  
Author(s):  
Srdan Verstovsek ◽  
Taghi Manshouri ◽  
Darrell Pilling ◽  
Carlos E. Bueso-Ramos ◽  
Kate J. Newberry ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Growth Factors ◽  
Stromal Cells ◽  
Primary Myelofibrosis ◽  
Neoplastic Disease ◽  
Immunodeficient Mice ◽  
Serum Amyloid P ◽  
Xenograft Mice ◽  
Amyloid P

Primary myelofibrosis (PMF) is a fatal neoplastic disease characterized by clonal myeloproliferation and progressive bone marrow (BM) fibrosis thought to be induced by mesenchymal stromal cells stimulated by overproduced growth factors. However, tissue fibrosis in other diseases is associated with monocyte-derived fibrocytes. Therefore, we sought to determine whether fibrocytes play a role in the induction of BM fibrosis in PMF. In this study, we show that BM from patients with PMF harbors an abundance of clonal, neoplastic collagen- and fibronectin-producing fibrocytes. Immunodeficient mice transplanted with myelofibrosis patients’ BM cells developed a lethal myelofibrosis-like phenotype. Treatment of the xenograft mice with the fibrocyte inhibitor serum amyloid P (SAP; pentraxin-2) significantly prolonged survival and slowed the development of BM fibrosis. Collectively, our data suggest that neoplastic fibrocytes contribute to the induction of BM fibrosis in PMF, and inhibiting fibrocyte differentiation with SAP may interfere with this process.

scholarly journals Bone marrow elements in cerebrospinal fluid: Review of literature with a case study

CytoJournal ◽  
2013 ◽  
Vol 10 ◽  
pp. 20 ◽  
Author(s):  
Anitha Ann Thomas ◽  
Felicia Tze Yee Goh
Keyword(s):  
Central Nervous System ◽  
Bone Marrow ◽  
Cerebrospinal Fluid ◽  
Nervous System ◽  
Young Children ◽  
Case Reports ◽  
Central Nervous System Infection ◽  
The Elderly ◽  
Review Of Literature

Presence of bone marrow elements in cerebrospinal fluid is rare. Journal publications on this topic are few and majority of them were written over a decade ago mostly as case reports in young children or the elderly. The increased cellularity and presence of myeloid precursors can be a pitfall and may be misdiagnosed as leukemia or lymphoma or central nervous system infection, when the specimen is actually not representative. With the intention to create awareness of potential pitfalls and avoid erroneous diagnoses, as well as adding on to the current photo archive of bone marrow elements in CSF, we present a recent case of bone marrow contaminants in the CSF of a 16-year-old girl.

Bone Marrow Angiogenesis in Chronic Lymphocytic Leukemia: Relationship to Classical and Modern Prognostic Factors.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4943-4943
Author(s):  
Lukas Smolej ◽  
Pavel Zak ◽  
Petra Benesova ◽  
David Belada ◽  
Monika Hrudkova ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Endothelial Cells ◽  
Prognostic Factors ◽  
Microvessel Density ◽  
Clinical Course ◽  
Hot Spot ◽  
Lymphocytic Leukemia ◽  
Control Group ◽  
Mutation Status ◽  
Genetic Abnormalities

Abstract Background: Angiogenesis is considered a potential prognostic factor in chronic lymphocytic leukemia (CLL). Elevated levels of various angiogenic factors have been identified in plasma or serum of CLL patients. However, results of studies assessing bone marrow neovascularization in CLL are controversial, in part due to different antibodies used for immunohistochemical identification of endothelial cells and different methods of assessing microvessel density (MVD). Moreover, there are insufficient data regarding relationship of bone marrow angiogenesis to other prognostic markers in CLL such as clinical stage, pattern of marrow infiltration, genetic abnormalities detected by fluorescent in situ hybridization (FISH), or mutation status of immunoglobulin heavy-chain variable-region genes (IgVH). Aims: To quantify MVD in bone marrow biopsies from CLL patients and control group and to assess its relationship to other prognostic factors. Methods: We analyzed bone marrow biopsy specimens from 22 untreated patients with CLL (16 males, 6 females, median age 62 years, range, 31–74). Control group consisted of 17 biopsies from individuals without evidence of malignant disease in bone marrow. Neovascularization was assessed using immunohistochemical staining of endothelial cells in bone marrow trephine biopsies with anti-CD34 monoclonal antibody. Microvessel density was assessed under light microscope equipped with image analysis software and calculated using hot spot method, i.e. identification of three loci with highest accumulation of microvessels under low (100x) magnification and counting microvessels in three high-power fields (400x magnification) per hot spot. MVD was expressed as mean number of microvessels per mm2. CLL cohort was further divided into subgroups according to clinical course (stable, n=11 vs. progressive, n=11), Rai stage (0, n=9 vs. I-IV, n=13), pattern of marrow infiltration (non-diffuse, n=11 vs. diffuse, n=11), genetic abnormalities (favourable, i.e. no abnormality or del13q14 as a sole aberration, n=10 vs. unfavourable, i.e. all other abnormalities, n=11), and IgVH mutation status (mutated, n=7 vs. unmutated, n=14). Results: MVD was significantly elevated in CLL group in comparison to controls (mean ± standard deviation [SD], 75.6 ± 50.6, 95% confidence interval [CI], 53.2–98.1/mm2 vs. 47.4 ± 21.8, 95% CI, 36.2–58.6/mm2, p=0.039). However, there were no significant MVD differences between CLL subgroups with regard to clinical course, pattern of marrow infiltration, Rai stage, FISH abnormalities or IgVH mutation status. Interestingly, when each subgroup was compared to controls, only patients with diffuse bone marrow infiltration (p=0.011), Rai stage I-IV (p=0.014) and mutated IgVH genes (p=0.019) had significantly increased MVD. Conclusions: This study shows that microvessel density is significantly elevated in CLL. However, this difference is maintained in three subgroups only: diffuse pattern of infiltration, mutated IgVH genes and Rai stage I-IV. We did not observe significant MVD differences between CLL subgroups with regard to classical or modern prognostic factors. Large prospective studies are necessary to confirm our results and elucidate the real clinical relevance of bone marrow angiogenesis in CLL.

Chronic Lymphocytic Leukemia (CLL) Cells Require Microenvironmental Stimuli to Resist Apoptosis through Activation of STAT3 Mediated by VEGF.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1069-1069
Author(s):  
Iris Gehrke ◽  
Julian Paesler ◽  
Rajesh Kumar Gandhirajan ◽  
Regina Razavi ◽  
Alexandra Filipovich ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Cell Survival ◽  
Lymphocytic Leukemia ◽  
Vegf Receptor ◽  
Mrna Levels ◽  
Activated State ◽  
Survival Effect

Abstract B-cell chronic lymphocytic leukemia (CLL) is characterized by an accumulation of mature, but incompetent B-cells due to a decrease of apoptosis rather than an increase in proliferation. Vascular endothelial growth factor (VEGF) has been suggested to play an important role in this so called apoptotic block. However, so far little is understood whether VEGF is acting mainly as a microenvironmental stimulus and/or whether CLL cells themselves contribute to the enhanced apoptotic resistance by maintaining an autocrine VEGF loop. Moreover, it is unknown by which mechanisms VEGF prevents apoptosis and whether this can be circumvented by inhibition of VEGF signaling. By quantitative real time PCR we found no significant difference in mRNA VEGF levels in B-cells from CLL patients and healthy donors after isolation from blood. In contrast, ELISA revealed clearly increased levels of secreted VEGF in plasma of CLL patients and in the supernatant under culture conditions compared to healthy individuals. In addition, we found the VEGF receptor 2 (VEGFR2), which is existent in CLL and healthy B-cells, in a phosphorylated, hence activated state, to a significantly higher extent in CLL cells as assessed by intracellular phospho flow cytometry. In conclusion, despite its expression in healthy B-cells VEGF does not seem to be secreted and therefore, no VEGF receptor phosphorylation takes place. Whereas CLL cells exhibit a long life span in vivo, they die rapidly in vitro, suggesting major survival factors being existent in the CLL cells microenvironment. We found levels of secreted VEGF in supernatant decreasing with time in culture, going along with decreasing levels of phosphorylated VEGFR2 and increasing cell death as assessed by Annexin V-FITC/PI staining. This further supports the role of VEGF in CLL cell survival. Coculturing primary CLL cells with the bone marrow stromal derived cell line HS5 dramatically increased VEGF transcription and secretion and improved cell survival. Hence, VEGF expression in CLL cells is not only mediated by autocrine, but also paracrine stimuli involving bone marrow stromal. Knocking down VEGF in HS5 cells and subsequent coculture with CLL cells might prove the major role of VEGF in this survival supporting coculture setting. Besides coculturing also supplement of culture medium with recombinant human VEGF (rhVEGF) increased survival, but to a lesser extent than coculture, indicating a direct cell-cell interaction as advantageous. Furthermore, we found a downregulation of anti apoptotic proteins, such as X-linked inhibitor of apoptosis protein (XIAP), myeloid cell leukemia 1 (MCL1) and BclXL upon VEGF stimulation. Also cyclinD1 was upregulated as seen by immunoblotting. We further tried to discover the underlying mechanism of how VEGF mediates its pro survival effect and found STAT3 to become phosphorylated on tyrosine 705 upon VEGF stimulation. In CLL STAT3 is known to be constitutively phosphorylated on serine 727. This phosphorylation is not sufficient to induce target gene expression though. We could show that Y705 phosphorylation of STAT3 is responsible for upregulation of anti apoptotic BCLXL and cyclinD1. A PCR array detecting mRNA levels of 84 transcription factors in untreated and VEGF stimulated CLL cells shall provide more information about mechanistical details how VEGF mediates it pro survival effect. Since VEGF seems to be a major player in CLL cell survival it might be a suitable target to overcome the apoptotic block. In first experiments we found an induction of apoptosis after neutralization of VEGF or inhibition of the VEGF receptor. This additionally highlights the severe importance of VEGF in the apoptotic block in CLL cells. Therefore, VEGF might serve as an excellent therapeutic target in CLL.

Prognostic Value of Angiogenesis Assessment in Chronic Lymphocytic Leukemia: More Data Needed.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4396-4396
Author(s):  
Darko Antic ◽  
Vladan Cokic ◽  
Marija Dencic Fekete ◽  
Maja Perunicic ◽  
Biljana Mihaljevic ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Lymphocytic Leukemia ◽  
Disease Progression ◽  
Clinical Course ◽  
Serum Levels ◽  
Lymphocytic Leukemia ◽  
Angiogenic Factor ◽  
Healthy Controls ◽  
Biological Features ◽  
Risk Of Disease

Abstract Abstract 4396 Introduction The association between angiogenesis and cancer progression in solid tumors has been documented, but its significance in chronic lymphocytic leukemia (CLL) has not been completely evaluated. Vascular endothelial growth factor /VEGF/ is the major pro-angiogenic factor in humans and his transduction pathway may be very active in CLL cells contributes to their enhanced survival. In this context VEGF can be additional tool for predicting the clinical course in early CLL. Patients and Methods To predict the risk of disease progression, we analyzed serum levels VEGF (sVEGF) using ELISA tehnique in 33 Binet stage A de novo CLL patients. In addition, We analyzed microvessel density (MVD) of the same patients using immunohistochemical staining with CD34 and vWf. Finally, we explored wheather changes of circulating VEGF concentrations and MVD reflected clinico-biological features of CLL (peripheral blood lymphocytosis (PBL), bone marrow (BM) histology, beta-2 microglobulin (β2m) level, lactat dehidrogenase (LDH) level) and kariotype abnormalities. Results The VEGF serum levels (sVEGF) was not significantly elevated (p=0.31) in CLL patients (mean: 70.9 pg/mL; range: 16–483) compared with and age- and sex-matched healthy controls (mean: 44.7 pg/mL; range: 22–69.2). sVEGF level positively correlated with elevated LDH level (p=0.008), but no correlation with other clinico-biological features was found. Bone marrow MVD was significantly higher (p<0.0001) in CLL patients (mean: 35.91 vessels/field ± 15.71) compared to controls (mean:8.27 vessels/field ±6.19). Also, there was a significant difference between MVD counts according to the antibody used. MVD was higher using CD34 vs vWF (CD34, 35.91 vessels/field ±15.7, vs vWF, 8.15 vessels/field ±4.65, p<0.0001). Bone marrow MVD detected by CD34 was significantlyhigher in patinents with CD38 expression more than 30% (p=0.006). However, no significant MVD differences were detected between CLL subgroups with regard to clinical course, pattern of marrow infiltration, Rai stage and FISH abnormalities. In univariate analysis sVEGF (p=0.018), Rai substages (p=0.027), PBL (p=0,030), β2m level (p=0.008) and diffuse bone marrow infiltration (p=0.006) were significantly associated with increased risk of disease progression. But, in multivariate analysis only sVEGF (p=0.002) and β2m level (p=0.008) retained their prognostic significance. Conclusions Serum VEGF level although not increased in comparasion with healthy controls, may improve the assessment of individual prognosis of patients with early CLL. Assessment of real clinical significance of bone marrow angiogenesis in CLL is required. Disclosures: No relevant conflicts of interest to declare.

Signal Transducer and Activator of Transcription (STAT)-3 Activates Nuclear Factor (NF)-κB in Primary Myelofibrosis (PMF) Bone Marrow Cells

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1742-1742
Author(s):  
Srdana Grgurevic ◽  
Srdan Verstovsek ◽  
Zhiming Liu ◽  
Taghi Manshouri ◽  
David Harris ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Conflicts Of Interest ◽  
Alternative Pathway ◽  
Primary Myelofibrosis ◽  
Canonical Pathway ◽  
Lymphocytic Leukemia ◽  
Janus Kinase ◽  
Low Density ◽  
Iκb Kinase

Abstract Abstract 1742 Primary myelofibrosis (PMF) is a stem cell–derived hematologic malignancy, characterized by an expansion of one or more myeloid lineage resulting in bone marrow (BM) hypercellularity, magakaryocyte proliferation with atypia, granulocytic proliferation, and reticulin and/or collagen fibrosis. An acquired activating mutation in Janus kinase 2 at codon V617F (JAK2V617F) is detected in BM cells of the majority of patients with PMF. Constitutively activated JAK2 induces phosphorylation and activation of STAT3. Phosphorylated STAT3 forms heterodimers, translocates to the nucleus, binds to DNA, activates STAT3-target genes, and induces production of cytokines that interact with the BM microenvironment. Hematopoietic stroma derived soluble factors provide PMF cells with survival advantage (Manshouri et al. Cancer Res 71: 3831, 2011) and, as reported previously, most of these factors activate NF-κB in a variety of cell types. NF-κB plays an important role in the survival and proliferation of normal and neoplastic cells. In several hematologic malignancies, the NF-κB p65/p50 dimers were found to be activated to variable degrees. The activation of NF-κB is mediated by either the canonical pathway or the alternative pathway. The canonical pathway is typically activated by extracellular signals that activate the β subunit of the IκB kinase (IKK) complex (IKKβ) that induces the phosphorylation and degradation of the NF-κB inhibitor IκBα. Following IκBα degradation, NF-κB heterodimers translocate to the nucleus and bind to DNA. We have recently found that in chronic lymphocytic leukemia (CLL) constitutively activated STAT3 induces the production of unphsophorylated (U) STAT3. U-STAT3 binds to the NF-κB dimers p65/p50 in competition with IκB and the U-STAT3/NF-κB complex shuttles to the nucleus where NF-κB binds to DNA and activates NF-κB-regulated genes (Liu et al. Mol Cancer Res 9: 507, 2011). Because in PMF constitutively activated JAK2 induces phosphorylation of STAT3 and this activated form of STAT3 induces the production of U-STAT3, we wondered whether, like in CLL, U-STAT3 activates NF-κB in PMF. To determine whether NF-κB is constitutively activated in PMF we obtained BM low density cells from untreated patients with PMF. First we studied low-density BM cells of 11 patients with PMF using the electrophoretic mobility shift assay (EMSA). Cells of all samples bound to a p65/NF-κB DNA-labeled probe and the addition of an unlabelled (cold) p65/NF-κB probe attenuated or completely eliminated the binding. Typically, NF-κB-DNA binding appears and disappears due to repeated degradation and re-synthesis of IκB and the consequent activation and inactivation of NF-κB, respectively. Because we found that NF-κB is constitutively activated in all PMF BM samples we hypothesized that, like in CLL cells, activation of NF-κB in PMF cells is induced by an IκB-unrelated mechanism as reported by Yang J et al. (Cancer Res 65:939, 2005). By using immunoprecipitation of two different PMF BM samples we determined that STAT3 binds to the RelA/p65 NF-κB protein, and by using EMSA we found that anti-STAT3, similar to anti- NF-κB p65 antibodies, attenuated the binding of PMF BM cell extract to the NF-κB DNA probe. Taken together, our data suggest that U-STAT3 binds the NF-κB dimers p65/p50 and constitutively activates NF-κB in PMF. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Chlorambucil-Induced Acute Interstitial Pneumonitis

2014 ◽  
Vol 2014 ◽  
pp. 1-5
Author(s):  
Hammad Shafqat ◽  
Adam J. Olszewski
Keyword(s):  
Systematic Review ◽  
Interstitial Pneumonitis ◽  
Pulmonary Toxicity ◽  
Alkylating Agent ◽  
Randomized Trials ◽  
Case Reports ◽  
Lymphocytic Leukemia ◽  
Mechanism Of Injury ◽  
Review Of Literature ◽  
Drug Induced

Chlorambucil is an alkylating agent commonly used in treatment of chronic lymphocytic leukemia (CLL). We report a case of interstitial pneumonitis developing in an 83-year-old man 1.5 months after completing a six-month course of chlorambucil for CLL. The interstitial pneumonitis responded to therapy with prednisone. We performed a systematic review of literature and identified 13 other case reports of chlorambucil-induced pulmonary toxicity, particularly interstitial pneumonitis. No unifying risk factor could be discerned and the mechanism of injury remains unknown. In contrast, major randomized trials of chlorambucil therapy in CLL have not reported interstitial pneumonitis as an adverse effect, which may be due to the rarity of the phenomenon or due to underreporting of events occurring after completion of treatment. Clinicians should consider drug-induced interstitial pneumonitis in the differential diagnosis of a suggestive syndrome developing even after discontinuation of chlorambucil.

scholarly journals Transgenic expression of JAK2V617F causes myeloproliferative disorders in mice

Blood ◽  
2008 ◽  
Vol 111 (10) ◽  
pp. 5109-5117 ◽  
Author(s):  
Shu Xing ◽  
Tina Ho Wanting ◽  
Wanming Zhao ◽  
Junfeng Ma ◽  
Shaofeng Wang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Transgenic Mice ◽  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Gene Promoter ◽  
Primary Myelofibrosis ◽  
Myeloproliferative Disorders ◽  
Transgenic Expression ◽  
Cell Counts

Abstract The JAK2V617F mutation was found in most patients with myeloproliferative disorders (MPDs), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis. We have generated transgenic mice expressing the mutated enzyme in the hematopoietic system driven by a vav gene promoter. The mice are viable and fertile. One line of the transgenic mice, which expressed a lower level of JAK2V617F, showed moderate elevations of blood cell counts, whereas another line with a higher level of JAK2V617F expression displayed marked increases in blood counts and developed phenotypes that closely resembled human essential thrombocythemia and polycythemia vera. The latter line of mice also developed primary myelofibrosis-like symptoms as they aged. The transgenic mice showed erythroid, megakaryocytic, and granulocytic hyperplasia in the bone marrow and spleen, displayed splenomegaly, and had reduced levels of plasma erythropoietin and thrombopoietin. They possessed an increased number of hematopoietic progenitor cells in peripheral blood, spleen, and bone marrow, and these cells formed autonomous colonies in the absence of growth factors and cytokines. The data show that JAK2V617F can cause MPDs in mice. Our study thus provides a mouse model to study the pathologic role of JAK2V617F and to develop treatment for MPDs.

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