To study the prevalence of the Val617Phe JAK2 mutation in familial cases of myeloproliferative disorder (MPD) and its possible implication as a predisposing genetic factor, we analyzed 72 families including 174 patients (
This study prospectively analysed the relationships between observed to vary according to the type and number of lymphimmunophenotypic and cytogenetic features of blast cells in oid lineage antigens expressed. 9 The expression of some of 432 acute non-lymphoblastic leukemias (ANLL) at presentation.these antigens also appeared to be related to recurrent cyto- The study was initiated in March 1992 by the Groupe d'Etude Immunologique des Leucémies (GEIL), a French multicentric Introduction group that collects data from over 40 centers in France and Belgium. The endpoint of the present analysis was 30 SepIn 1988, the morphologic, immunologic and cytogenetic tember 1994. Patients eligible for the study met the following working classification (MIC) of acute non-lymphoblastic leucriteria: established diagnosis of ANLL and collection of a sufkemia (ANLL) 1 underlined the correlations between some ficient number of blast cells for both immunophenotype and recurrent specific cytogenetic abnormalities and defined cytosuccessful cytogenetic analysis. M0-ANLL were defined as logic subgroups. At that time, the relationships between cytopreviously reported. 2 FAB data were collected from each genetic features identified in ANLL and the immunophenotype center's cytology laboratory. of blast cells remained poorly characterised. During the last 10 years, immunophenotypic analysis of ANLL blast cells has provided new information and become a powerful tool in Immunological phenotyping assigning undifferentiated acute leukaemia to the myeloid lineage. 2 Meanwhile, investigation of lymphoid lineage antigens Mononuclear cells were recovered from heparinized bone on blast cells from a large number of ANLL has demonstrated marrow (391 cases) or peripheral blood (41 cases) collected the high immunophenotypic heterogeneity of morphologically at diagnosis. The percentage of blast cells after separation on and cytogenetically well-defined diseases. [3][4][5][6][7][8] a Ficoll gradient was higher than 50% in M2 and M4 subtypes Molecular analyses attempting to correlate these immunoand higher than 80% in the remaining cases. The immunophenotypic features to their genotypic counterpart did not phenotype was performed by flow cytometry on blast cells demonstrate any strict correlation between the rearrangement gated on their abnormal light scatter characteristics, using of immunoglobulin and T cell receptor genes and the monoclonal antibodies for the following antigens: CD9 expression of lymphoid lineage antigens on ANLL blast (IOB2), CD11b (FD11), CD13 (MY7), CD14 (UCHM1), cells. 3,9-11 However, the prevalence of genotypic changes was CD15a (SMY15a), CD16 (Leu11b), CD18 (IOT18), CD33 (MY9), CD34 (BI-3C5), CD35 (44-D), CD36 (OKM5), CDw65 (VIM2), CD41 (P2), CD42 (SZ2), T lymphoid differentiation
Chronic myeloproliferative disorders (CMPD) are rare diseases of the bone marrow characterised by a clonal proliferation of one or several myeloid lineages. Familial clustering are regularly reported suggesting a role for inherited factors. To adress this issue, we collected with the help of a large network of haematologists clinical data and blood samples of 78 families defined by the presence of at least two affected subjects with one of the four CMPD: polycythemia vera, essential thombocythemia, chronic myeloid leukemia and agnogenic myeloid metaplasia. A total of 176 affected subjects including 83 polycythemia vera, 70 essential thrombocythemia, 12 chronic myeloid leukemia and 11 agnogenic myeloid metaplasia were recruited. 449 asymptomatic relatives, mainly first-degrees, were collected and among them 11%were carriers of endogenous erythroid colonies with normal blood counts. Phenotypic spectrum within families was either homogenous (46/78) or heterogeneous (32/78) and the main association (25/32) was polycythemia vera and essential thrombocythemia. A few cases of changes in disease phenotype was also observed during the course of CMPD. Clinical and haematological data of affected subjects at diagnosis and during the course of the disease were similar to sporadic CMPD. However, a marked anticipation of approximatively 20 years/generation at onset age was observed. No excess of carcinomas was noted either in affected subjects or relatives. An excess of acute leukemias, however, was noted in relatives. We did not show evidence of known environmental factors such as exposition to ionic radiations or chemical solvents. Familial cases were restricted to a single generation in 33 families. Occurence was vertical in 45 families involving 2 generations in 36 and 3 generations in 9. In those familial cases consistent with a dominant inheritance, we exluded molecular abnormalities of VHL and EpoR genes involved in particular forms of familial and congenital polycythemia. In conclusion, the analysis of these 78 familial CMPD cases highlights that (i) the observation of mixed phenotypes in a large proportion is consistent with the theory that MPD arise from clonal expansion of a pluripotent hematopoietic precursor cell (ii) no environmental factor is clearly involved in the onset of CMPD and (iii) the observation of familial aggregations and the low incidence of the pathology suggest the implication of genetic predisposition factors in the occurence of myeloproliferative disorders. This large collection of multiplex families enables us to initiate genome-wide linkage analysis.
We have recently reported that the somatic V617F JAK2 mutation could be heterogeneously distributed within families with MPD (Bellanne-Chantelot et al, Blood, 108, 346). These families are characterized by at least 1 affected patient with the mutation (JAK2-positive) and 1 or 2 affected relatives without the mutation (JAK2-negative). We have analyzed 18 such families: 3 with polycythemia vera (PV), 7 with essential thrombocythemia (ET), 1 with myelofibrosis and myeloid metapasia (MMM) and 7 families with 2 types of MPD (PV and ET). The median age at diagnosis was not significantly different between the 2 groups considering PV and ET independently. The analysis of 25 patients with ET (11 JAK2-positive and 14 JAK2-negative patients) revealed no difference in the platelet count (950x109/L versus 1004x109/L, respectively). Hemoglobin level and hematocrit were higher in the group of JAK2-positive patients: (144 g/L versus 130 g/L, p=0.009) and (43% vs 39%, p=0.02). Likewise in the same group, endogenous erythroid colonies were more significantly frequent compared to JAK2-negative patient group. As for PV, the sole difference observed between the 2 groups of patients (10 JAK2-positive and 4 JAK2-negative patients) was the higher level of white blood cells (13x109/L vs 6.5x109/L, p=0.01) in the group of PV JAK2-positive patients. All the 39 patients but 2 were treated. Among the JAK2-positive patients, one PV patient developed an acute myeloblastic leukemia and another one a secondary MMM. In the JAK2-negative group, a ET patient developed an acute megakaryoblastic leukemia. Death occured in 7/22 JAK2-positive patients and in 4/20 negative patients. We were able to confirm after a delay of 4 to 7 years the V617F JAK2 genotype in a subset of affected patients. The proportion of the mutant JAK2 allele has increased in a range of 5 to 50% in patients initially diagnosed with the V617F JAK2 mutation. By contrast, the mutation remains absent in patients initially JAK2-negative. We therefore hypothesize that other somatic mutations may be implicated in the development of MPD in JAK2-negative patients in these families. It has been recently suggested that alterations in cytokine receptors, the erythropoietin receptor (EPOR) and thrombopoietin receptor (MPL), might lead to activation of the JAK-STAT signaling pathway in patients negative for the V617F mutation. We have screened by sequencing two regions known to be involved in receptor dimerization (transmembrane domain) and JAK2 binding (juxtamembrane domain). No mutations were identified in these critical regions of EPOR and MPL. In conclusion, this study highlights the variable clinical expression of MPD within these families heterogeneous for the V617F JAK2 mutation. The hematological phenotype seems restricted to a specific lineage in the group of JAK2-negative patients. However, the course of the disease was similar in both groups. The absence of mutations in EPOR and MPL cytokine receptors raised the issue of other genes that are not JAK2-mediated and that might be involved in the occurrence of MPD within these families.
1978 To study the evolution and prognosis in familial cases of myeloproliferative neoplasms (MPN), we collected clinical data and blood samples from 94 families defined by the presence of at least two affected subjects with one MPN. A total of 228 subjects including 99 polycythemia vera (PV), 104 essential thrombocythemia (ET), 14 primary myelofibrosis (PMF) and 11 chronic myeloid leukaemia (CML) were recruited. Occurrence was vertical in 63 families involving 2 generations in 48, 3 generations in 13, and two other families implicating respectively 4 and 5 generations. The distribution of MPN was most compatible with autosomal dominant inheritance. Phenotypic spectrum within families was either homogenous (56/94) or heterogeneous (35/94) and the main association (21/35) was PV and ET. Clinical and haematological data of affected subjects at diagnosis were similar to sporadic MPN. The V617F JAK2 mutation was found in 87% of patients with PV, in 59% of patients with ET, in 64% with PMF and in none patient with CML. 99 PV patients were studied (median age, 54 years; median follow-up, 12 years). Overall survival was 83% at 10 years and 37% at 20 years. At time of analysis 53% were alive; death was due to the hematologic malignancy in 74% of cases. Progression to acute leukemia and secondary myelofibrosis risks were respectively 21% and 20%, after a median time of 14 years (5,4-32,5) and 13 years (4,7-31). No difference in frequency of transformation in acute leukemia was observed between the JAK2 positive (23%) and JAK2 negative (20%) PV patients. Interestingly, none of JAK2-negative PV patients progressed to myelofibrosis, whereas 13 (20%) of JAK2-positive patients suffered from this adverse evolution. A high JAK2 allele burden was correlated with transformation to myelofibrosis. Of 49 patients with < 50% JAK2 mutated allele burden, only 2 (5%) developed myelofibrosis, whereas of 23 patients with ≥ 50% allele burden, 11 (48%) developed this complication (p<0,0001). Thrombosis occurred in 42% of PV patients, arterial in 19 (50%) cases, venous in 16 (42%), and 2 patients suffered both arterial and venous thrombosis. Hemorrhagic manifestations occurred in 2% of cases. Among the 104 ET (median age, 45 years; median follow-up, 8 years), overall survival was 83% at 10 years and 57% at 20 years. At time of analysis 83% were alive, 70% of deaths were related to the MPN. The risks of progression to acute leukemia and myelofibrosis were 10% and 13%, after a median time of 7,4 years (0,8-24) and 16 years (2,5-20,5) respectively. In particular, two non-related ET patients evolved rapidly after diagnosis, developing acute leukemia within the first year. We found no difference in frequency of transformation to acute leukemia or myelofibrosis according to JAK2 status. 32% ET patients suffered from thrombosis, arterial in 18 (60%) of cases and venous in 10(33%). Hemorrhagic manifestations occurred in 3% of cases. In the 14 PMF patients (median age, 53 years; median follow-up, 8 years), overall survival was 46% at 10 years. Transformation risk to acute leukemia was 23% with a median time of 26 months (1-50). Considering the whole population, occurrence of thrombosis was correlated with JAK2 mutational status, with 18% of any thrombosis in the JAK2-negative group and 37% in the JAK2-positive group (p=0.009). Among these, 12 (26%) patients developed deep venous thrombosis such as portal venous thrombosis or Budd-Chiari syndrome. In conclusion, the analysis of these 94 familial myeloproliferative neoplasms cases highlights that the presence of JAK2 mutation is associated with transformation to myelofibrosis for familial PV patients, and with a more frequent occurrence of thrombosis in the entire population. Patients with familial PV have a comparable prognosis to non familial PV. But, in our cohort, there seems to be an excess mortality of familial ET patients when compared to sporadic ET without clear correlation with JAK2 mutational status. Other genetic events involved in familial myeloproliferative neoplasms could explain this phenomenon. Disclosures: No relevant conflicts of interest to declare.
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