Interleukin-13- and Tansforming Growth Factor-β- Producing Mast Cells Are Associated with Fibrosis in Bone Marrow

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3112-3112
Author(s):  
Shoko Nakayama ◽  
Taiji Yokote ◽  
Nobuya Hiraoka ◽  
Toshikazu Akioka ◽  
Takuji Miyoshi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mast Cell ◽  
Growth Factor ◽  
Mast Cells ◽  
Mutual Aid ◽  
Mast Cell Tryptase ◽  
Bone Marrow Fibrosis ◽  
Significant Difference ◽  
Grade 3 ◽  
Marrow Fibrosis

Abstract Background: Fibrosis in bone marrow is a lethal condition, which currently has no effective treatments. Transforming growth factor (TGF)-β, produced by megakaryocytes and blasts in myelodisplastic syndrome (MDS) with bone marrow fibrosis, is reportedly linked to this condition; however, the underlying mechanism of fibrosis in bone marrow remains uncharacterized. Recently, interleukin (IL)-13- and TGF-β- producing mast cells have been reported to participate in the development of fibrosis in certain fibrotic diseases, such as the IgG4-related diseases. Aim: This study aimed to investigate the pathogenesis of fibrosis in bone marrow through histological examination of mast cell infiltration and the expression of cytokines associated with fibrosis. Methods: We analyzed 22 bone marrow samples from patients with confirmed fibrosis; of these, eight patients had been diagnosed with primary myelofibrosis (PMF), five with post-polycythemia vera (PV)/essential thrombocythemia (ET) MF, and nine with MDS with bone marrow fibrosis. These were compared with 15 control bone marrow samples, using immunohistochemical staining of mast cell tryptase, IL-13, and TGF-β, as well as using dual immunofluorescence assays for the following pairs: mast cell tryptase/ IL-13 and mast cell tryptase/ TGF-β. The extent of fibrosis in bone marrow samples was analyzed by Masson's trichrome staining and silver impregnation staining. Results: Among eight PMF cases, five were identified as grade 2 and three as grade 3; among five post-PV/ET cases, four were grade 2 and one was grade 3; and among nine MDS patients with bone marrow fibrosis, six were grade 2 and three were grade 3. Grading was performed according to the European consensus on grading of bone marrow fibrosis. The number of mast cells in bone marrow samples was significantly higher in cases with fibrosis than in controls, as analyzed by t-test (p < 0.0001) (Figure 1A). Each group of bone marrow samples with fibrosis (primary MF, post-PV/ET MF, and MDS with bone marrow fibrosis) also had significantly more infiltrating mast cells than controls, using multiple comparison with the Tukey's honestly significant difference test (p = 0.0470, < 0.0001, 0.0005, respectively) (Figure 1B). Bone marrow samples with higher fibrotic grades exhibited greater amounts of infiltrating mast cells; for instance, bone marrows with fibrotic grades of 2 or 3 had more infiltrating mast cells than controls (p = 0.0010, < 0.0001, respectively). In addition, bone marrows with a fibrotic grade of 3 had more infiltrating mast cells than those with fibrotic grade 2 (p = 0.0010) (Figure 2). Mast cells were positive for IL-13 (Figure 3) and TGF-β (Figure 4) in dual immunofluorescence assays of mast cell tryptase and IL-13 or TGF-β; however, megakaryocytes and blasts of MDS with bone marrow fibrosis were negative for IL-13 and TGF-β. Conclusion: Based on these findings, we hypothesize that IL-13- and TGF-β- producing mast cells are key elements in the development of fibrosis in bone marrow. Therefore, mast cells are potential therapeutic targets for the treatment of fibrosis in bone marrow. Disclosures Nakayama: the promotion and mutual aid corporation for private schools of Japan: Research Funding.

Imatinib reduces bone marrow fibrosis and overwhelms the adverse prognostic impact of reticulin formation in patients with chronic myeloid leukaemia

2016 ◽  
Vol 69 (9) ◽  
pp. 810-816 ◽  
Author(s):  
Eda Tanrikulu Simsek ◽  
Ahmet Emre Eskazan ◽  
Mahir Cengiz ◽  
Muhlis Cem Ar ◽  
Seda Ekizoglu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Imatinib Therapy ◽  
Imatinib Treatment ◽  
Prognostic Impact ◽  
Bone Marrow Fibrosis ◽  
Significant Difference ◽  
Grade Ii ◽  
Marrow Fibrosis

AimsBefore the era of tyrosine kinase inhibitors (TKIs), the presence of bone marrow fibrosis (MF) in patients with chronic myeloid leukaemia (CML) has been established as a poor prognostic factor. The aim of the present study was to evaluate the effects of imatinib treatment on MF and the prognostic significance of MF at this new era of CML therapy.MethodsThe study cohort consisted of 135 patients with CML who were exposed to imatinib. The grades of MF pre and post imatinib together with cytogenetic and molecular responses were evaluated.ResultsSevere MF (grade II–III) was observed in 44 (33%) patients prior to imatinib therapy, and in 8 (8%) after 12 months of imatinib treatment (p=0.001). The complete cytogenetic response (CCyR) rates at 12 months did not differ according to the pre-imatinib MF grades, and CCyR rates in patients with grades 0, I, II and III MF were 36/47 (76.5%), 26/33 (78.7%), 12/23 (52.1%) and 7/10 (70%), respectively (p=0.127). There was no significant difference between patients with or without CCyR at 12 months of imatinib regarding grades of MF (p=0.785). The distribution of the major molecular response rates at 18 months according to pre-treatment grades of MF were determined as grade 0 in 38/45 (84.4%), grade I in 21/28 (75%), grade II in 14/21 (66.6%) and grade III in 7/10 (70%) (p=0.112). There was no significant difference in overall survival rates between initial MF mild (grade 0–I) and severe (grade II–III) groups (p=0.278).ConclusionsAccording to our findings, MF regresses with imatinib therapy over time, and the MF grades at diagnosis do not have a negative impact on the responses to imatinib treatment. Therefore, the adverse prognostic impact of the MF among patients with CML seems to disappear in the era of the TKIs.

scholarly journals Rescue of W-associated mast cell defects in W/Wv bone marrow cells by ectopic expression of normal and mutant epidermal growth factor receptors

Blood ◽  
1993 ◽  
Vol 82 (5) ◽  
pp. 1463-1470
Author(s):  
T von Ruden ◽  
L Stingl ◽  
A Ullrich ◽  
EF Wagner
Keyword(s):  
Signal Transduction ◽  
Bone Marrow ◽  
Mast Cell ◽  
Growth Factor ◽  
Mast Cells ◽  
Epidermal Growth Factor ◽  
Bone Marrow Cells ◽  
Ectopic Expression ◽  
Tissue Type ◽  
Epidermal Growth

Abstract The normal human epidermal growth factor receptor (EGF-R) (HERc), a chimeric EGF-R/v-erbB (HERerbB) receptor, and the ligand-independent oncogenic EGF-R variant (v-erbB) were used to correct the mast cell defects in W/Wv bone marrow (BM) cells. In culture, all three receptor molecules transduced functional mitogenic signals in infected interleukin-3 (IL-3)-dependent bone marrow-derived mast cells (BMMCs) and enabled their differentiation into safranin-positive mast cells resembling connective tissue-type mast cells (CTMCs). Furthermore, expression of these receptors restored the capacity of W/Wv BMMCs to colonize the peritoneal cavity of mast cell-deficient W/Wv mice where they differentiated to safranin-positive cells with similar frequencies as wild-type BMMCs. These experiments show that expression of normal and mutant EGF-Rs in W/Wv BM cells is able to complement the function of the c-kit-encoded Steel factor receptor (SLF-R) in mast cell development. We conclude that signal transduction by normal and mutant EGF-Rs in murine hematopoietic cells apparently involves components also used by the SLF-R, which suggests that these receptors use overlapping pathways for signal transduction.

Thrombopoietin Regulates Proliferation and Maturation of Murine Mast Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1707-1707
Author(s):  
Giovanni Migliaccio ◽  
Barbara Ghinassi ◽  
Lucia Centurione ◽  
Maria Zingariello ◽  
Lucia Bianchi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mast Cell ◽  
Cell Differentiation ◽  
Growth Factor ◽  
Mast Cells ◽  
Wild Type ◽  
Connective Tissues ◽  
Immature Cells

Abstract Megakaryocytopoiesis is regulated by extrinsic (interaction of the growth factor thrombopoietin, TPO with its receptor Mpl) and intrinsic (interaction between the trascription factors GATA-1 and Fog-1) factors. The observation that mice impaired for GATA-1 expression (i.e. harbouring the GATA-1low mutation) are defective not only in megakaryocyte maturation but also in mast cell differentiation (Migliaccio et al. J Exp Med197:281, 2003), led us to investigate whether TPO might control mast cell differentiation as well. We first observed that mice genetically unable to responde to TPO (Mplnull mice) express in the connective tissues 5 times more mast cells than their normal littermates. Then, we analysed the effects on mast cell differentiation of in vivo treatment with TPO. Normal mice, and their GATA-1low littermates, were injected i.p. with TPO (100 μg/kg/day per 5 days, kindly provided by Kirin Brewery, Japan) and the number of immature (Toluidinepos) and mature (AlcianBlue/Saphraninepos) mast cells present in the connective tissues of the animals, as well as the frequency of GATA-1pos and TUNELpos mast cells, was evaluated 14 days after treatment. In wild-type animals, TPO reduced the presence of GATA-1 in mast cells (by immuno-histochemistry) and increased the number of immature cells (from 320±28 to 852±60) and of those undergoing apoptosis (from 16±1 to 600±43). In contrast, in GATA-1low animals, TPO-treatment induced the expression of GATA-1 in mast cells while decreased the number of immature cells (from 1100±72 to 427±29) as well as that of apoptotic cells (from 600±45 to 60±2). The role of TPO on mast cell differentiation were further confirmed by the analysis of the effects exerted by the growth factor on in vitro differentiation of bone marrow derived mast cells (BMMC). In these experiments, wild type bone marrow and spleen cells were cultured for 21 days with SCF and IL-3 with or without TPO and BMMC differentiation measured on the basis of the number of cells expressing the phenotype c-kithigh/CD34high and FcεRIpos. In cultures stimulated with SCF and IL-3, all the cells expressed the phenotype c-kithigh/CD34high and FcεRIpos. In contrast, in cultures supplemented also with SCF, IL-3 and TPO, only 25% of the cells were c-kithigh/CD34high and none of them was FcεRIpos. These results establish a role for TPO in the control of mast cell differentiation (possibly by modulating the GATA-1 content of the cells) and unveil further similarities between the mechanism(s) controlling megakaryocyte and mast cell differentiation.

Decoding Bone Marrow Fibrosis in Myelodysplastic Syndrome

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1985-1985
Author(s):  
Megan Melody ◽  
Najla H Al Ali ◽  
Ling Zhang ◽  
Hanadi Ramadan ◽  
Eric Padron ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Research Funding ◽  
Somatic Mutations ◽  
Bone Marrow Aspirate ◽  
Bone Marrow Fibrosis ◽  
Advisory Committees ◽  
Significant Difference ◽  
Baseline Characteristics ◽  
Grade 3 ◽  
Severe Fibrosis

Abstract Background Bone marrow fibrosis (BMF) is observed in 10-20% of patients diagnosed with MDS. A study conducted at the University of Pavia, Italy evaluated 180 cases of MDS with varying grades of BMF and found that the presence of grade 2-3 BMF in MDS (graded by European classification) was associated with worse outcomes, especially in patients with lower risk MDS, however there remains little data pertaining to the treatment and outcomes in the MDS-F patient population. The primary objective of this study is to examine a large MDS patient population to further determine the relationship between BMF and survival outcomes in the context of new risk stratification models. Methods All bone marrow aspirate and biopsy reports, obtained at the time of diagnosis or prior to any therapy, in the Moffitt Cancer Center MDS database were reviewed and the degree of BMF was determined using the European classification system. Patients with less than 5% myeloblasts and grade 2 or 3 BMF were identified and these bone marrow aspirate and biopsies were reviewed by two hematopathologists (LZ and JMB) to confirm the grade of fibrosis reported. Patients were then divided into two groups: grade 0-2 BMF and severe BMF (grade 3). These two groups were compared to evaluate differences in clinical characteristics, response to treatment and survival. NexGen sequencing was available for 251 patients and distribution of acquired somatic mutations were compared between grade 0-2 BMF and grade 3 BMF. Results There were 2357 cases included in this analysis of which 2237 (95%) were determined to have grade 0-2 BMF and 120 (5 %) to have grade 3 BMF. Table-1 summarizes baseline characteristics. There was no statistical difference in age at diagnosis, gender, or race. A greater percentage of patients with severe BMF (39%) met the criteria for poor/very poor IPSS-R score category than patients with grade 0-2 BMF (29%), p = 0.011. Complex karyotype was observed more frequently among patients with severe fibrosis (23% versus 15%, p = 0.031). Patients with severe BMF also had a higher incidence of elevated LDH (51%) than patients with grade 0-2 BMF (33%), P < 0.005. The median overall survival (OS) was 38.7 months (mo) for grade 0-2 BMF and 23.1mo for grade 3 BMF, p < 0.005. When examined by revised IPSS (R-IPSS), severe BMF only impacted OS among the lower risk group. The median OS in patients with very low/low R-IPSS risk was 47mo in patients with severe BMF compared to 77 for those with grade 0-2 BMF, p = 0.015. In multivariable analysis, adjusting for age and R-IPSS, severe BMF was independently associated with inferior OS (HR 1.7, P 0.01). The rate of AML transformation was 28% in both the severe and grade 0-2 BMF groups, p = 0.98. Eighty patients with severe BMF were treated with hypomethylating agents (HMA). The overall response, by IWG 2006 criteria, of HI or better was 30% among patients with severe BMF compared to 32% of patients with grade 0-2 BMF, p 0.4. Among patients with severe BMF treated with lenalidomide (n=30), 25% of patients had HI response compared to 16% in patients with grade 0-2 BMF, p 0.9. The median OS for the 100 patients with severe BMF who did not undergo allogenic SCT was 23mo compared to 30mo for the 19 patients with severe BMF who did undergo allogenic SCT, p 0.29 Among somatic gene mutations, SF3B1 mutation was observed in 14% of grade 0-2 and 0% of grade 3 fibrosis. However, SRSF2 was present in 35.7% of patients with grade 3 fibrosis and only 9.7% of patients with grade 0-2 BMF, p .009. There was no statistically significant difference in the rate of occurrence of TP53 and RUNX1 mutations between the grade 0-2 BMF and the grade 3 BMF groups. In addition, there was no significant difference in the rate of occurrence of JAK2 mutation across the two groups. (table-2) Conclusions In our MDS cohort, only the presence of severe BMF (grade 3) was associated with worse outcome with reduced overall survival namely among patients with very low/low R-IPSS disease, whereas BMF grade did not impact response to HMA or lenalidomide treatment. SRSF2 gene mutation occurred with greater frequency among patients with severe fibrosis. Table 1 Baseline characteristics Table 1. Baseline characteristics Table 2 Acquired Somatic Mutations Table 2. Acquired Somatic Mutations Disclosures Sweet: Incyte Corporation: Research Funding; Ariad: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Pfizer: Speakers Bureau; Karyopharm: Honoraria, Research Funding. Bennett:Celgne: Membership on an entity's Board of Directors or advisory committees. Komrokji:Incyte: Consultancy; Novartis: Consultancy, Speakers Bureau; Boehringer-Ingelheim: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Proteasome Inhibitor Bortezomib Can Inhibit Bone Marrow Fibrosis Development in a Murine Model of Myelofibrosis.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2582-2582 ◽  
Author(s):  
Orianne Wagner-Ballon ◽  
Thomas Gastinne ◽  
Micheline Tulliez ◽  
Catherine Lacout ◽  
Didier Pisani ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Growth Factor ◽  
Proteasome Inhibitor ◽  
Transforming Growth Factor ◽  
Mice Model ◽  
Bone Marrow Fibrosis ◽  
Bortezomib Treatment ◽  
Pathway Activation ◽  
Tgf Β1 ◽  
Marrow Fibrosis

Abstract Several lines of evidence obtained from idiopathic myelofibrosis (IM) studies are in favour of a crucial role of the NF-κB pathway activation in myelofibrosis induction. It has been demonstrated that megakaryocytes, monocytes but also CD34+ cells from IM patients present a spontaneous NF-κB pathway activation associated with transforming growth factor-β1 (TGF-β1) secretion. This growth factor has been previously shown as the main fibrogenic cytokine involved in the myelofibrosis development. Mice exposed to high systemic levels of thrombopoietin (TPO) mediated by a retroviral vector (TPOhigh mice) develop a myeloproliferative disorder featuring numerous aspects of the human disease including bone marrow fibrosis, extramedullary hematopoiesis and dysmegakaryopoiesis. Moreover, TPOhigh mice display high plasma levels of IL-1α suggesting that the NF-κB pathway may play a role in this model of fibrosis. We then conducted a study to investigate whether NF-κB inhibition in this mice model could have an impact on myelofibrosis development using the proteasome inhibitor bortezomib. One month after engraftment with TPO-overexpressing hematopoietic cells, 2 groups of 20 immunocompetent C57BL/6J mice displaying similar myeloproliferation induced by TPO overexpression were constituted. Mice engrafted were treated twice a week, with either bortezomib (1 mg/kg) or a placebo for 4 weeks. At the end of this protocol, mice from both groups were examined for histological and haematological analysis including TGF-β1 and IL-1α levels determination. Here, we demonstrate that: i) the NF-κB pathway is activated in TPOhigh spleen cells and bortezomib treatment is able to inhibit this activation; ii) bortezomib treatment is able to decrease plasma concentration of TGF-β1 and IL-1α in mice as well as TGF-β1 content in extracellular fluids of marrow and spleen; iii) myelofibrosis development is inhibited after bortezomib treatment. These results emphasize the interest of developing bortezomib treatment in IM patients.

Rapid Regression of Bone Marrow Fibrosis after Dose-Reduced Allogeneic Stem Cell Transplantation in Patients with Myelofibrosis.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 374-374
Author(s):  
Nicolaus Kroeger ◽  
Juergen Thiele ◽  
Axel Zander ◽  
Michael Kvasnicka
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Growth Factor ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Bone Marrow Fibrosis ◽  
Myeloid Metaplasia ◽  
Bone Marrow Histology ◽  
Marrow Fibrosis

Abstract Myelofibrosis with myeloid metaplasia [MMM] is a myeloproliferative disease of which bone marrow histology is characterized by substantial collagen fibrosis and osteosclerosis. Bone marrow histology changes in MMM are reactive and cytokine mediated. Studies suggested a pathogenic role of transforming growth factor β [TGF-β], platelet derived growth factor, and basic fibroblast growth factor. In the current study we investigated the dynamic and kinetic of fibrosis regression in 18 patients with myelofibrosis who underwent allogeneic stem cell transplantation after a dose-reduced conditioning. The conditioning regimen consisted of Busulfan 10 mg/kg, Fludarabin 180 mg/m2, and Antithymocyte globulin 30 – 60 mg/kg followed by peripheral stem cell transplantation (SCT). 18 patients with a median age of 45 [range 35 to 64] were included and bone marrow histology was investigated prior SCT, between day+30 and +40 after engraftment, on day+100, and 1 year after stem cell transplantation. The grading of myelofibrosis [MF] was performed according to the recently published European Consensus on Grading Bone Marrow Fibrosis [Thiele et al., Haematologica2005;90:1125–1132]. This consensus distinguishes between: MF - 0 Scattered linear reticulin with no intersections [cross-overs] corresponding to normal bone marrow MF - 1 Loose network of reticulin with many intersections, especially in perivascular areas MF - 2 Diffuse and dense increase in reticulin with extensive intersections, occasionally with only focal bundles of collagen and/or focal osteosclerosis MF - 3 Diffuse and dense increase in reticulin with extensive intersections with coarse bundles of collagen, often associated with significant osteosclerosis At time of transplantation all patients suffered from advanced myelofibrosis 2° [39 %] or 3° [61 %], resulting in a median MF grade of 3 [range 2–3]. After engraftment on day+30 a regression of MF grade to a median of 2 [range 0–3] was observed. Grade 2 or less was observed in 80 % and grade 1 or 0 in 40 % of the patients. On day+100 the median grade of MF was 1 [range 0–3] and 93 % of the patients had an MF-grade of 2 or less, while 73 % of the patients had MF grade-1 or 0. One year after transplantation the median MF-grade was 0 [range 0–2] and 100 % of the patients had a MF-grade of 2 or less and 92 % of the patients had MF grade 1 or 0. We conclude that allogeneic stem cell transplantation after a dose-reduced conditioning induces a rapid and nearly complete regression of bone marrow fibrosis within the first year after transplantation.

scholarly journals Systemic Mastocytosis Presenting with a Prominent B Lymphocyte Proliferation in the Bone Marrow and Extensive Fibrosis of the Spleen

2007 ◽  
Vol 23 (3) ◽  
pp. 167-171
Author(s):  
Nalan Neşe ◽  
Seçkin Çağcaron;ırgan ◽  
Yešim Ertan ◽  
Ayhan Sönmez ◽  
Saliha Soydan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mast Cell ◽  
Mast Cells ◽  
Hodgkin Lymphoma ◽  
Lymphocyte Proliferation ◽  
B Lymphocyte ◽  
Systemic Mastocytosis ◽  
Low Grade ◽  
Mast Cell Tryptase ◽  
Non Hodgkin Lymphoma

Systemic mastocytosis is a disease characterized by multifocal mast cell proliferation in the bone marrow or other extracutaneous organs. Because of loosely scattered and hypo-/agranular mast cells, the diagnosis is sometimes very difficult. In the bone marrow, mast cell infiltration may be associated with prominent lymphoid infiltration leading to a misdiagnosis of a low grade non-Hodgkin lymphoma.A 49-year-old woman presented with right arm and leg pain, psychiatric symptoms, and diarrhea for four years. Physical examination and laboratory investigation revealed hepatosplenomegaly, anemia, mild thrombocytosis, mild leucocytosis and lymphocytosis. In the bone marrow biopsy, there was a prominent B lymphocyte proliferation reminiscent of a low grade non-Hodgkin lymphoma/leukemia and there were some spindle cells aggregates in paratrabecular location. The consecutive bone marrow biopsies were similar to the first. The subsequent splenectomy specimen exhibited striking fibrosis. In the lymph node sections, there was marginal zone hyperplasia.Multifocal accumulations of mast cells were strongly positive with mast cell tryptase and CD117 on immunohistochemical staining, though no metachromasia was identified in Giemsa and Toluidine Blue stained aspirates and tissue sections, probably due to hypo-/agranulation of mast cells.The case was presented to emphasize the importance of the antibody to mast cell tryptase in the diagnosis of mastocytosis and to discuss problems of differential diagnosis of systemic mastocytosis.

Quantitative Analysis of Growth Factor Production in the Mechanism of Fibrosis in Agnogenic Myeloid Metaplasia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4272-4272
Author(s):  
Jen-Chin Wang ◽  
Tsong S. Chang ◽  
Amit Goldberg ◽  
Allan D. Novetsky ◽  
Jeffrey Lipton
Keyword(s):  
Bone Marrow ◽  
Growth Factors ◽  
Quantitative Analysis ◽  
Growth Factor ◽  
Bone Marrow Fibrosis ◽  
Myeloid Metaplasia ◽  
Agnogenic Myeloid Metaplasia ◽  
Growth Factor Production ◽  
Tgf Β1 ◽  
Marrow Fibrosis

Abstract There are previous reports that growth factors including TGF-β1, PDGF and FGF produced by megakaryocytes are responsible for the etiology of fibrosis in agnogenic myeloid metaplasia (AMM). Due to the technical difficulty in isolating enough megakaryocytes from the inaspirable bone marrow from patients with AMM, a quantitative analysis of these growth factors produced by the megakaryocytes and correlated to the degree of myelofibrosis has not been able to be performed. The present study employed the cell culture technique to grow megakaryocytes from blood CD 34+ cells and then perform the quantitative analysis of these growth factors, compared with other sources such as monocyte-macrophage lineages and correlated to the degree of bone marrow fibrosis. We found TGF-β1, PDGF and FGF produced by the megakaryocytes were significantly elevated in AMM compared with normal controls (p&lt;0.05) and TGF-β1 was more abundantly produced than PDGF or FGF. While these growth factors are several fold elevated in AMM compared with other MPD including essential thrombocythemia (ET), polycythemia vera (PV), it was not statistically significant. A quantitative analysis of these growth factors produced by the CD 14+ cells in the blood and bone marrow showed that these growth factors were not significantly elevated in AMM compared with other MPD or controls and were significantly elevated only in some patients (defined as elevation of more than 2 SD of the controls). The correlation of these growth factors produced by the megakaryocytes or monocyte-macrophage lineages with degree of myelofibrosis in 12 patients with AMM were r=0.73 and 0.23 respectively (Non parametric (Spearman) correlation with two-tailed analysis was used to calculate the correlation). We concluded: In AMM, these fibrosing growth factors are mainly produced by the megakaryocytes and in some patients, monocyte-macrophage lineages may contribute to the production of these growth factor production. TGF-β1 is more abundantly produced from the megakaryocytes than PDGF or FGF confirming TGF-β1 is the most important fibrosing growth factor in the pathogenesis of myelofibrosis in AMM. A statistically significant correlation of the growth factor and degree of myelofibrosis in AMM suggests that these fibroing growth factors produced by the megakaryocytes are main etiology of bone marrow fibrosis in AMM.

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