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PubMed1994

[TGF-beta and platelet].

In the present paper, we investigated the pathophysiological implication of TGF-beta from megakaryocytes or megakaryoblasts in the development of myelofibrosis. In the bone marrow of myelofibrosis, proliferation of megakaryocytes is often noticed. We therefore investigated the TGF-beta expression in the bone marrow megakaryocytes from 12 chronic myeloproliferative disorder patients with myelofibrosis by immunohistochemical analysis. About all the specimen showed strong positivity for TGF-beta. In order to examine whether megakaryoblasts produce TGF-beta, we then measured TGF-beta activity in the conditioned medium (CM) of megakaryoblasts from a patient with acute megakaryoblastic leukemia who had profound myelofibrosis. The CM showed strong collagen synthesis stimulating activity which was nullified by addition of anti TGF-beta antibody. Since TGF-beta exists as latent form in platelets, TGF-beta was considered to be altered from active to latent form during megakaryocytes differentiation. In this context, MEG-01, a megakaryoblastic cell line which produces active TGF-beta was underwent differentiation to produce platelet-like bleb with TPA treatment. During the differentiation, MEG-01 showed the decrease of active TGF-beta production and increase of latent TGF-beta together with the production of LTBP. These results suggest that megakaryoblasts produce active TGF-beta and may may cause myelofibrosis, while more differentiated megakaryocytes produce latent TGF-beta. Mechanism by which megakaryoblast escape from negative autocrine of active TGF-beta was also investigated. MEG-01 was found to express mutated p53 which is considered to be responsible for impaired signal transduction of TGF-beta.

Blood Platelets↗
PubMed1990

Target cell of leukemic transformation in acute megakaryoblastic leukemia.

Acute megakaryoblastic leukemia (AMkL) is a newly defined acute leukemia in which the differentiation of proliferating blasts is arrested at the megakaryocytic precursor stage. In order to clarify whether a target cell of leukemic transformation in AMkL is a cell committed to megakaryocytic lineage, or a multipotential stem cell, we examined AMkL patients with regard to: a) the presence of myelodyplastic features in residual erythroid and granulocytic cells, b) coexistence of myeloperoxidase (MPO)-positive blasts with megakaryoblasts, and c) the presence of the same chromosomal abnormality in erythroid and granuloid colony-forming cells as seen in megakaryoblasts. Regarding the former two items, results were compared with those from megakaryoblastic crisis of chronic myelocytic leukemia (CML-MkBC) and transient myeloproliferative disorder in Down syndrome (DS-TMD), which are thought to be multipotential stem cell disorders. Among 18 patients with AMkL, three, all complicating myelofibrosis, had marked myelodysplastic changes of erythroid series and/or granulocytic series. In 4 out of 7 patients with CML-MkBC, 5 out of 8 patients with DS-TMD, and 7 out of 18 patients with AMkL, MPO-positive blasts, even though rare, were observed in addition to PPO-positive blasts. All except one of these patients with AMkL also showed complicating myelofibrosis. In one case of AMkL with myelofibrosis, chromosomal analysis of cultured cells of individual colonies revealed that all the analysable metaphases from both CFU-GM and BFU-E had the same chromosomal abnormality as megakaryoblasts. This study has clarified that a considerable proportion of AMkL cases, particularly those with complicating myelofibrosis or showing acute myelofibrosis, arise against the background of a multipotential stem cell disorder, even if blasts are exclusively megakaryocytic in phenotype.

Cell Transformation, Neoplastic↗
PubMed2005

Progenitor cell trafficking in physiologic conditions and in myeloproliferative diseases: quantification of CD34+ cells by polymerase chain reaction.

BACKGROUND AND OBJECTIVES: Previous studies using flow cytometry have shown that CD34+ cell trafficking is increased in patients with chronic idiopathic myelofibrosis. Few data exist on physiologic CD34 + cell trafficking and the quantification of very low cell ranges requires reliable and sensitive measurement techniques. The aim of this study was to establish a quantitative polymerase chain reaction (PCR) technique for studying CD34+ cell trafficking in physiologic conditions, and in patients with myeloproliferative diseases. DESIGN AND METHODS: CD34+ cell trafficking was measured in 56 controls [(healthy controls (n=21), patients with ischemic cardiopathy (n=21), patients with secondary thrombocytosis or erythrocytosis (n=14)], and in 37 untreated patients with myeloproliferative diseases diagnosed according to the WHO-criteria [(essential thrombocythemia (n=10), polycythemia vera (n=14) and chronic idiopathic myelofibrosis (n=13)]. Quantitative PCR was used to determine CD34 mRNA expression in peripheral blood samples. RESULTS: Physiologic CD34 mRNA expression ranges were determined in the healthy control group. Mean CD34 mRNA expression was within the physiologic range in patients with ischemic cardiopathy, secondary thrombocytosis or erythrocytosis, essential thrombocythemia and polycythemia vera (p=0.146), but was significantly increased in patients with chronic idiopathic myelofibrosis (p<0.001). When analyzed individually, 12/13 patients with chronic idiopathic myelofibrosis and 3/14 patients with polycythemia vera showed CD34 mRNA expression above the physiologic range. INTERPRETATION AND CONCLUSIONS: This is a first report about CD34+ cell trafficking measured by quantitative PCR. Quantitative PCR is a reliable method suitable for the quantification of very low cell populations. Our study confirms the significant increase of CD34+ cell trafficking in patients with chronic idiopathic myelofibrosis, and in a subset of patients with polycythemia vera. Prospective studies are underway to characterize these circulating CD34+ cells and to investigate their role in the pathophysiology of myeloproliferative diseases.

Adult↗
PubMed1995

The impact of interferon versus busulfan therapy on the reticulin stain-measured fibrosis in CML--a comparative morphometric study on sequential trephine biopsies.

To evaluate treatment-related changes of the reticulin stain-measured fibrosis in Ph(1+)-CML, a clinicopathological study was performed on sequential trephine biopsies of the bone marrow following either interferon (IFN) or busulfan (BU) monotherapy. Using the monoclonal antibody CD61 for the identification of megakaryopoiesis and Gomori's silver impregnation method, number of megakaryocytes and density of argyrophilic (reticulin and collagen) fibers were determined by morphometry. We studied specimens from 26 patients with IFN-alpha 2b (including nine patients with additional IFN gamma) therapy and from 23 patients who had received BU. In both groups, repeated bone marrow biopsies (total 125) revealed a significant increase in the fiber content, as well as in the number of megakaryocytes during treatment. To assess the dynamics of myelofibrosis more precisely, computation of differences in the degree of fiber density between the first and last examination was carried out. Regarding the considerable variations in the biopsy intervals, a so-called myelofibrosis progression index (MPI) was calculated. Following this rationale, we were able to demonstrate that, in comparison to the BU-group, speed of progression of bone marrow fibrosis was significantly increased in CML patients treated with IFN. Preliminary statistical analysis indicated a relationship between myelofibrosis on admission, which was always associated with increased growth of megakaryocytes, and the MPI with survival. Even when these parameters were regarded, prognosis was significantly more favorable in the IFN-treated patients. The failure of IFN and BU to inhibit the evolution of myelofibrosis may be related to several conversely acting pathomechanisms. Among others, the inability of both therapeutic agents to reduce the number of megakaryocytes more effectively should be taken into consideration.

Adolescent↗
PubMed2000

Effects of interferon and hydroxyurea on bone marrow fibrosis in chronic myelogenous leukaemia: a comparative retrospective multicentre histological and clinical study.

A retrospective multicentre clinicopathological study was performed on sequential bone marrow trephine biopsies in 100 patients with Ph1+-chronic myelogenous leukaemia (CML) to elucidate the effect of interferon (IFN) alpha 2b and hydroxyurea (HU) treatment on myelofibrosis and megakaryopoiesis. According to strictly defined therapeutic regimens, 38 patients received IFN as monotherapy, 23 patients a combination of IFN and HU and 39 patients HU only. Using standardized intervals of biopsies and histochemical and morphometric methods, a significant increase in reticulin fibre density and in the number of CD61+ megakaryocytes was detectable in the majority of IFN-treated patients. To a lesser degree, these changes were also expressed in the cohort with a combined IFN and HU regimen. In contrast to these findings, in the group of patients with HU as single-agent treatment, a stable state or reversal of myelofibrosis was detectable together with corresponding changes in megakaryopoiesis. Further evaluations revealed that these effects had occurred within the first year, mostly after 6 months of treatment, and were prominently expressed in those patients with a slight to relevant grade of myelofibrosis at presentation. In conclusion, this study provides persuasive evidence that monotherapy by IFN exerts a fibrogenic effect, while HU treatment seems to prevent and even resolves bone marrow fibrosis in CML. Probably, in relation to the complex pathomechanisms responsible for the generation of myelofibrosis, the changing content of reticulin fibres was usually accompanied by corresponding alterations in the number of CD61+ megakaryocytes, including atypical microforms and precursor cells.

Adult↗
PubMed2006

Age and hemoglobin level emerge as most important clinical prognostic parameters in patients with osteomyelofibrosis: introduction of a simplified prognostic score.

The course of disease in patients with myelofibrosis is highly variable, with survival ranging from few months to many years. Several prognostic models have been established, with the LILLE score now most commonly used. However, in recent series, the latter scoring system repeatedly failed to discriminate patients with intermediate and poor prognosis. In the present study, we re-evaluated previous prognostic models in a separate patient population. We have studied 107 patients with myelofibrosis and correlated clinical parameters at the time of diagnosis with survival. Previous scoring systems were applied to allocate patients to subgroups with distinct prognosis. Most previous scoring systems failed to clearly discriminate an intermediate and poor prognostic group. By contrast, age and hemoglobin level emerged as most significant parameters in multivariate analysis. By allocating one risk point each for hemoglobin < 10 g/dl and age >60 years, three subgroups of patients with distinct prognosis could be identified in our cohort. The overall model and the difference between each of the subgroups were statistically significant in a training group, a test group, the overall cohort of patients and the group of patients with chronic idiopathic myelofibrosis. In summary, we propose an alternative prognostic model for patients with myelofibrosis that reliably identifies three groups of patients with highly different outcome. This is in contrast to previous prognostic scores, in which the poor prognosis group was often very small and/or could not be consistently differentiated from patients with an intermediate prognosis.

Adult↗
PubMed1999

Early postoperative complications of splenectomy for hematologic disease.

Splenectomy may be indicated in a variety of hematologic diseases for diagnostic reasons, therapeutic reasons, or both. Most reviews reveal a high proportion of procedures performed as part of the staging process for Hodgkin disease. Splenectomy for myelofibrosis has been associated with an increased postoperative complication rate. Other determinants of morbidity have been splenic weight and operative blood loss. The authors reviewed a series of 83 adult patients from a prospective database established in 1991 to determine the incidence of early postoperative complications associated with splenectomy for hematologic disease and to analyze patient characteristics that may predict their occurrence. Morbidity that occurred within 30 days of splenectomy was considered to be an early postoperative complication. Operative estimated blood loss and incidence of postoperative complications were correlated with patient age, preoperative platelet count, splenic weight, and diagnosis of myelofibrosis as regression covariates. Indications for splenectomy were therapeutic in 76 patients (92%). Median splenic weight was 760 g, and 22 patients had massive splenomegaly. Patients with splenic weight more than 1,500 g had a significantly higher median estimated blood loss (300 ml; p = 0.02). Splenic weight was the main determinant of estimated blood loss in a multiple linear regression analysis (p = 0.02). Twenty-two patients (27%) experienced postoperative complications and five of those patients died (6%). Patients with myelofibrosis had the highest incidence of complications (50%) and the highest postoperative mortality (21%; p = 0.04). In a logistic regression model, estimated blood loss was the only variable significantly correlated with postoperative complications (p = 0.02). Splenectomy for hematologic disease is associated with an acceptable early postoperative complication rate, even when the indication is predominantly therapeutic. Patients at particularly high risk include those with elevated operative blood loss, massive splenomegaly, and myelofibrosis.

Adult↗
PubMed1990

Clinical significance of serum pro-collagen III in chronic myeloproliferative disorders.

Pro-collagen III (PC III) has been proposed as a useful value for diagnosis and follow-up of myeloproliferative disorders. A significant difference is observed between polycythaemia vera (PV) and essential thrombocythaemias (ET) on one hand, and the pure erythrocytoses (PE) on the other hand, but a large overlap makes this test of low diagnostic value. High values are observed in primary and post-PV myelofibrosis, but excessive PC III levels in active PV are not predictive of evolution toward myelofibrosis. PC III level is lower in myelo-suppressed patients (32P, or hydroxy-urea) than in active cases or in patients treated by phlebotomies. We conclude that PC III measurement is of low diagnostic value for discriminating PV and PE, does not appear to allow short-term prediction of evolution to myelofibrosis, but may be useful to evaluate the role of treatment in delaying progression of PV toward myelofibrosis.

Aged↗
PubMed1981

[Congenital deficiency of platelet alpha-granules and medullary reticulinic fibrosis. Physiopathogenic hypothesis (author's transl)].

Hematological investigations of two propositus from a family with congenital thrombopathia characterised by a moderate thrombopenia and a specific platelet alpha granule deficiency revealed that the thrombopathia was associated with a constitutive reticulinic myelofibrosis, without any sign of evolutivity. This association led us to present an hypothesis to explain the genesis of this myelofibrosis. This hypothesis is based on the potential role of a mitogenic factor(s) synthetized in megakaryocytes and transported normally by platelets in alpha granules, to induce fibroblastic proliferation and increased synthesis of collagen type III by bone marrow. This myelofibrosis is similar to that found in most of myeloproliferative disorders at some step of evolutivity. In these diseases myelofibrosis is associated with qualitative and quantitative abnormalities of platelets and megakaryocytes. These abnormalities give elements to sustain our hypothesis.

Blood Platelet Disorders↗
PubMed2006

The role of JAK2 V617F mutation, spontaneous erythropoiesis and megakaryocytopoiesis, hypersensitive platelets, activated leukocytes, and endothelial cells in the etiology of thrombotic manifestations in polycythemia vera and essential thrombocythemia.

Exaggerated erythropoiesis and megakaryocytopoiesis are present at a variable extent in polycythemia vera (PV) and essential thrombocythemia (ET). With the recent discovery of the V617F mutation in the Janus kinase 2 (JAK2) tyrosine kinase in almost all cases of PV and in a subset of patients with ET, studies are now pending to assess the role of this mutation in the hematopoietic cell activation process and/or in the occurrence of thromboses in ET and PV. The JAK2 V617F point mutation makes the normal hematopoietic progenitor cells hypersensitive to thrombopoietin, erythropoietin, and myeloid progenitor cells, leading to trilinear hematopoietic myeloproliferation. This will have three main clinical consequences during long-term follow-up. First, spontaneous growth of enlarged mature megakaryocytes in ET/PV with overproduction of hypersensitive platelets results in a broad spectrum of platelet-mediated microvascular circulatory disturbances, which are very sensitive to low-dose aspirin. Second, spontaneous growth of erythropoiesis with the overproduction of erythrocytes leads to classic PV with increased hemoglobin, hematocrit, and red cell mass. This is associated with a high frequency of major arterial and venous thrombotic complications in addition to platelet-mediated microvascular circulatory disturbances of thrombocythemia. Third, the slowly progressive myeloid (granulocytic) metaplasia in bone marrow and spleen is complicated by secondary myelofibrosis caused by a megakaryocytic/granulocytic cytokine storm in about one fourth to one third of JAK2 V617F-positive PV patients after long-term follow-up, with no tendency of leukemic transformation as long as they are not treated with myelosuppressive agents. Randomized clinical trials directly comparing phlebotomy versus hydroxyurea or interferon alpha versus hydroxyurea in PV with progressive disease are lacking. Heterozygous V617F mutation is enough to produce the clinical picture of ET with a slight tendency to increased hemoglobin and hematocrit (early PV mimicking ET). Homozygous V617F mutation is associated with the clinical picture of classic PV and with a higher tendency to secondary myelofibrosis, but with no increased leukemia unless other biological or genetic factors come into play, such as myelosuppressive agents or the acquisition of additional biologic or genetic defects. Depending on the biological background of individual patients, heterozygous and homozygous JAK2 V617F ET/PV may preferentially induce myeloid metaplasia with myelofibrosis with a relative suppression of megakaryocytic and erythropoietic myeloproliferation leading to clinical pictures of fibrotic chronic idiopathic myelofibrosis (CIMF) or agnogenic myeloid metaplasia. The main conclusion is that JAK2 V617F is a 100% specific clue to a new distinct clonal myeloproliferative disorder. JAK2 V617F-positive ET/PV and CIMF should be distinguished from wild-type JAK2 ET, rare cases of PV, and CIMF, and should be evaluated during life-long follow-up.

Blood Platelets↗
PubMed2005

Variegation of the phenotype induced by the Gata1low mutation in mice of different genetic backgrounds.

All mice harboring the X-linked Gata1low mutation in a predominantly CD1 background are born anemic and thrombocytopenic. They recover from anemia at 1 month of age but remain thrombocytopenic all their life and develop myelofibrosis, a syndrome similar to human idiopathic myelofibrosis, at 12 months. The effects of the genetic background on the myelofibrosis developed by Gata1low mice was assessed by introducing the mutation, by standard genetic approaches, in the C57BL/6 and DBA/2 backgrounds and by analyzing the phenotype of the different mutants at 12 to 13 (by histology) and 16 to 20 (by cytofluorimetry) months of age. Although all the Gata1low mice developed fibrosis at 12 to 13 months, variegations were observed in the severity of the phenotype expressed by mutants of different backgrounds. In C57BL/6 mice, the mutation was no longer inherited in a Mendelian fashion, and fibrosis was associated with massive osteosclerosis. Instead, DBA/2 mutants, although severely anemic, expressed limited fibrosis and osteosclerosis and did not present tear-drop poikilocytes in blood or extramedullary hemopoiesis in liver up to 20 months of age. We propose that the variegation in myelofibrosis expressed by Gata1low mutants of different strains might represent a model to study the variability of the clinical picture of the human disease.

Aging↗
PubMed2000

Efficacy of pipobroman in the treatment of polycythemia vera: long-term results in 163 patients.

BACKGROUND AND OBJECTIVES: Polycythemia vera (PV) is a myeloproliferative disorder, characterized by the expansion of the red cell mass. Our purpose was to evaluate the efficacy of pipobroman (PB) in the long-term control of PV and to assess early and late events. DESIGN AND METHODS: From June 1975 to December 1997, 163 untreated patients with PV (median age 57 years, range 30-82) were treated with PB in a single Institute for a median follow-up of 120 months. The diagnosis was made according to the Polycythemia Vera Study Group criteria. PB was given at the dose of 1 mg/kg/day until hematologic response (hematocrit < 45% and platelets < 400x109/L) and of 0.3-0.6 mg/kg/day as maintenance therapy. RESULTS: Hematologic remission was achieved in 94% of patients in a median time of 13 weeks (range 6-48). Median overall survival was 215 months, with a standardized mortality ratio of 1.7. The cumulative risk of death was 11%, 22%, and 26% at 7, 10, and 12 years, respectively. The incidence of thrombotic events was 18.4x105 person-year and the cumulative risk was 6%, 11%, 16%, and 20% at 3, 7, 10, and 12 years respectively. Acute leukemia occurred in 11 patients, myelofibrosis in 7, and solid tumors in 11. The 10-year cumulative risk of leukemia, myelofibrosis, and solid tumors was 5%, 4%, and 8%, respectively. In the logistic analysis age over 65 (p = 0.0001) and thrombotic events at diagnosis (p = 0.001) were significantly correlated with a higher risk of death. Female gender (p = 0.02) and age over 65 (p = 0.01) significantly influenced the occurrence of thrombotic complications. Age was the only significant risk factor for leukemia (p = 0.04) and for solid tumors (p = 0.03), while the duration of PB treatment did not influence these risks. No significant risk factor was demonstrated for myelofibrosis. INTERPRETATION AND CONCLUSIONS: This study demonstrates in a large series of patients, observed for a long period, that pipobroman is effective in the long-term control of PV. The risk of early thrombotic complications at 3 years is 6% and the 10-year risk of acute leukemia, late myelofibrosis, and solid tumors is 5%, 4%, and 8%, respectively. The duration of pipobroman treatment did not correlate with these events.

Administration, Oral↗
PubMed1998

Systemic transforming growth factor-beta in patients with bone marrow fibrosis--pathophysiological implications.

Idiopathic myelofibrosis (IMF) and secondary myelofibrosis (MF) are characterized by bone marrow (BM) fibrosis, neoangiogenesis, and increased extracellular matrix (ECM) proteins. These characteristics may be partially attributed to transforming growth factor beta (TGF-beta), a cytokine produced by monocytes. In myelofibrosis, monocytes are increased and activated with concomitant up-regulation of intracytoplasmic TGF-beta. We have therefore determined systemic TGF-beta in patients with either BM fibrosis: IMF, n = 18; MF, n = 16; or without BM fibrosis: hematologic disorders with normal platelets (n = 31); high platelets (n = 9); or normal controls (n = 27). Compared with nonfibrosis sera, there was significant TGF-beta elevation in BM fibrosis sera (P < 0.0001). Most (>80%) of the TGF-beta is active and belongs to the-beta1 isoform. In situ hybridization and immunohistochemical analyses in BM biopsy sections showed a marked increase in TGF-beta1 only in patients with fibrosis. Moreover, TGF-beta protein was detected mainly in myelomonocytic-like predominant areas. To determine if another functionally similar cytokine, basic fibroblast growth factor (bFGF), may be important to BM fibrosis, we quantitated sera levels and found elevation in 57% compared with 100% elevation for TGF-beta. The data indicate that irrespective of etiology, systemic TGF-beta is elevated in patients with BM fibrosis. TGF-beta likely plays an important role in the development of BM fibrosis. The study also provides a significant parameter for early therapeutic intervention in BM fibrosis.

Adult↗
PubMed2003

Results of imatinib mesylate therapy in patients with refractory or recurrent acute myeloid leukemia, high-risk myelodysplastic syndrome, and myeloproliferative disorders.

BACKGROUND: Imatinib mesylate is a selective tyrosine kinase inhibitor of c-abl, bcr/abl, c-kit, and platelet-derived growth factor-receptor (PDGF-R). c-kit is expressed in most patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) and PDGF has been implicated in the pathogenesis of myeloproliferative disorders (MPD). METHODS: The authors investigated the efficacy of imatinib in patients with these disorders. Forty-eight patients with AML (n = 10), MDS (n = 8), myelofibrosis (n = 18), atypical chronic myeloid leukemia (CML; n = 7), chronic myelomonocytic leukemia (CMML; n = 3), or polycythemia vera (n = 2) were treated with imatinib 400 mg daily. RESULTS: None of the patients with AML or MDS responded. Among patients with myelofibrosis, 10 of 14 patients with splenomegaly (71%) had a 30% or greater reduction in spleen size, 1 patient had trilineage hematologic improvement, 2 had erythroid hematologic improvement, and 1 had improvement in platelet count. One patient with atypical CML had erythroid hematologic improvement. Both patients with polycythemia vera needed fewer phlebotomies (from 2-3 per year to none during the 8 months of therapy and from 3-6 per year to 1 during 9 months of therapy). None of the three patients with CMML responded. Treatment was well tolerated. The side effects were similar to those observed in patients with CML. CONCLUSIONS: Within these small subgroups of disease types, single-agent imatinib did not achieve a significant clinical response among patients with AML, MDS, atypical CML, or CMML without PDGF-R fusion genes. Preliminary data on polycythemia vera are promising and deserve further investigation. Responses among myelofibrosis patients were minor. Therefore, a combination treatment regimen including imatinib may be more effective.

Adult↗
PubMed1982

Fibrous long spacing-like fibers in the bone marrow of myloproliferative disorder.

Bone marrow obtained at autopsy from four cases of primary myelofibrosis and four cases of chronic myelogenous leukemia, was studied electron microscopically. In all the cases of primary myelofibrosis, the excess of collagen fibers in the bone marrow showed mostly about 2,000 A diameter and 1,000 A periodicity, i.e. fibrous long spacing (FLS)-like fibers. These FLS-like fibers were also seen in secondary myelofibrosis in three of the four cases of chronic myelogenous leukemia. These fibers were abundant around fibroblasts and small blood vessels. An apparent continuity between the dark bands of FLS-like fibers and the basement membrane material around small blood vessels was also revealed. Moreover, it was observed that these dark bands of FLS-like fibers contained acid mucopolysaccharides.

Adult↗
PubMed2002

Successful treatment with imatinib mesylate of a CML patient in megakaryoblastic crisis with severe fibrosis.

The prognosis of patients with chronic myeloid leukemia in blastic crisis (CML-BC) remains extremely poor, and multiagent chemotherapy regimens commonly used to treat acute leukemia offer only short-term benefits. Therefore, the advent of the novel molecularly targeted anticancer agent imatinib mesylate is a breakthrough in CML therapy. We present a CML patient in megakaryoblastic crisis with severe myelofibrosis, who was treated with imatinib at a dosage of 400 mg/day and achieved complete remission together with a marked regression of myelofibrosis after 1 month. The effect of imatinib on the long-term prognosis remains unclear, although the agent is clearly a promising drug for treating CML-BC even in cases of myelofibrosis.

Adult↗
PubMed2001

[Chronic myeloproliferative disorders. The new WHO classification].

Except for chronic myelogenous leukemia (CML), chronic myeloproliferative disorders (CMPDs) include as main subtypes polycythemia vera (PV), chronic idiopathic myelofibrosis (IMF), and essential thrombocythemia (ET). A common finding in CMPDs is a clonal evolution associated with a significantly variable course, which may be complicated by thrombocythemia, (secondary) myelofibrosis, and finally acceleration (unstable phase) that merges into blastic crisis. New therapeutic modalities (chemo- and interferon therapy, bone marrow and stem cell transplantation) which were developed in the last decade and the striking differences in survival amongst the different subtypes warrant not only an unequivocal distinction from reactive and allied disorders, but a clear-cut classification as well. For this reason, a synoptical approach is essential including clinical data and, as a major diagnostic tool, a bone marrow biopsy. This concept finds expression in the new WHO classification, which also includes as rare subtypes chronic neutrophilic leukemia, eosinophilic leukemia, chronic hypereosinophilic syndrome, and finally unclassifiable entities. Histopathology of bone marrow biopsies reveals specific findings, in particular concerning megakaryopoiesis, which are characteristic for the different subtypes. These features facilitate the still controversially discussed differentiation of thrombocythemia that is frequently present, as is the case in initial (prefibrotic) IMF from ET. Moreover, in addition to clinical findings,the associated heterogeneity of bone marrow morphology indicates a stepwise evolution of the disease process and thus exerts a significant impact on survival, i.e., in CML regarding erythropoiesis and myelofibrosis and in IMF extent of myeloid metaplasia.

Bone Marrow↗
PubMedDate not supplied

Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders.

BACKGROUND: Human myeloproliferative disorders form a range of clonal haematological malignant diseases, the main members of which are polycythaemia vera, essential thrombocythaemia, and idiopathic myelofibrosis. The molecular pathogenesis of these disorders is unknown, but tyrosine kinases have been implicated in several related disorders. We investigated the role of the cytoplasmic tyrosine kinase JAK2 in patients with a myeloproliferative disorder. METHODS: We obtained DNA samples from patients with polycythaemia vera, essential thrombocythaemia, or idiopathic myelofibrosis. The coding exons of JAK2 were bidirectionally sequenced from peripheral-blood granulocytes, T cells, or both. Allele-specific PCR, molecular cytogenetic studies, microsatellite PCR, Affymetrix single nucleotide polymorphism array analyses, and colony assays were undertaken on subgroups of patients. FINDINGS: A single point mutation (Val617Phe) was identified in JAK2 in 71 (97%) of 73 patients with polycythaemia vera, 29 (57%) of 51 with essential thrombocythaemia, and eight (50%) of 16 with idiopathic myelofibrosis. The mutation is acquired, is present in a variable proportion of granulocytes, alters a highly conserved valine present in the negative regulatory JH2 domain, and is predicted to dysregulate kinase activity. It was heterozygous in most patients, homozygous in a subset as a result of mitotic recombination, and arose in a multipotent progenitor capable of giving rise to erythroid and myeloid cells. The mutation was present in all erythropoietin-independent erythroid colonies. INTERPRETATION: A single acquired mutation of JAK2 was noted in more than half of patients with a myeloproliferative disorder. Its presence in all erythropoietin-independent erythroid colonies demonstrates a link with growth factor hypersensitivity, a key biological feature of these disorders. RELEVANCE TO PRACTICE: Identification of the Val617Phe JAK2 mutation lays the foundation for new approaches to the diagnosis, classification, and treatment of myeloproliferative disorders.

Chromosomes, Human, Pair 9↗