ABSTRACT
Fundamento y objetivo: La leucemia mieloide crónica atípica (LMCa) y la leucemia neutrofílica crónica (LNC) presentan gran similitud clínico-analítica. El objetivo del estudio fue determinar el estado mutacional de SETBP1 y CSF3Ren dichas entidades. Pacientes y método: Se analizó el estado mutacional de SETBP1 y CSF3R en 7 pacientes con LMCa (n = 3), LNC (n = 1) y neoplasia mieloproliferativa (NMP) inclasificable (n = 3). Adicionalmente se estudiaron los genes ASXL1,SRSF2, IDH1/2, DNMT3A y RUNX1. Resultados: Se detectaron mutaciones en SETBP1 (G870S y G872R) en 2 pacientes con NMP inclasificable; uno de ellos presentó, además, mutaciones en SRSF2 (P95H) y ASXL1 (E635fs). El paciente afectado de LNC presentó mutaciones en CSFR3 (T618I), SETBP1 (G870S) y SRSF2 (P95H). Ningún paciente catalogado como LMCa mostró mutación de SETBP1 o CSF3R. De los pacientes con mutaciones, uno evolucionó a leucemia aguda mieloblástica y 2 presentaron progresión de la enfermedad sin llegar a documentarse transformación a leucemia. Conclusión: El conocimiento de las alteraciones moleculares involucradas en estas raras enfermedades es útil en el diagnóstico y podría tener repercusión tanto en el pronóstico como en el tratamiento (AU)
Background and objective: Atypical chronic myeloid leukemia (aCML) and chronic neutrophilic leukemia (CNL) display similar clinical and hematological characteristics. The objective of the present study was to determine the mutational status of SETBP1 and CSF3R in these diseases. Patients and method: The mutational status of SETBP1 and CSF3R was studied in 7 patients with aCML (n = 3), CNL (n = 1) and unclassifiable myeloproliferative neoplasms (MPN-u) (n = 3). Additionally, mutations in ASXL1,SRSF2, IDH1/2, DNMT3A, and RUNX1 were also analyzed. Results: SETBP1 mutations (G870S and G872R) were detected in 2 patients with MPN-u, and one of them also presented mutations in SRSF2 (P95H) and ASXL1 (E635fs). The CNL case showed mutations in CSFR3(T618I), SETBP1 (G870S) and SRSF2 (P95H). No patient classified as aCML had mutations in SETBP1or CSF3R. One of the patients with mutations evolved to acute myeloid leukemia, while the other 2 had disease progression without transformation to overt leukemia. Conclusion: The knowledge of the molecular alterations involved in these rare diseases is useful in the diagnosis and may have an impact on both prognosis and therapy (AU)
Subject(s)
Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative/genetics , Leukemia, Neutrophilic, Chronic/genetics , Mutation/genetics , Myeloproliferative Disorders/genetics , Myelodysplastic-Myeloproliferative Diseases/geneticsABSTRACT
Introducción y objetivo: Recientemente se han publicado 2 nuevos índices pronósticos de supervivencia y de trombosis, el International Prognostic Score for Essential Thrombocythemia (IPSET) y el IPSET-Thrombosis, respectivamente, basados en la edad, la cifra de leucocitos, la historia de trombosis, la presencia de factores de riesgo cardiovascular y el estado mutacional de JAK2. El objetivo del presente estudio fue analizar las características clínico-biológicas en el momento del diagnóstico y durante la evolución en una serie homogénea de pacientes con trombocitemia esencial (TE), así como analizar los factores asociados a la supervivencia y a la trombosis y la utilidad de dichos índices pronósticos. Pacientes y métodos: Se revisaron los datos analíticos y clínicos y el estado mutacional de JAK2, MPL y calreticulina de 214 pacientes diagnosticados de TE consecutivamente en un único centro entre 1985 y 2012. Se clasificaron los pacientes de acuerdo con la estratificación de riesgo clásica, el IPSET y el IPSET-Thrombosis. Resultados: Con una mediana de seguimiento de 6,9 años, el análisis multivariado no puso de manifiesto ningún factor asociado a la supervivencia global. Los antecedentes trombóticos y la leucocitosis > 10 × 109/l se asociaron a la supervivencia libre de trombosis (SLT). En nuestra serie, los sistemas pronósticos IPSET de supervivencia y de trombosis no aportan información de mayor relevancia clínica respecto al pronóstico asociado con los factores de riesgo trombótico clásico. Conclusión: Los antecedentes de trombosis y la leucocitosis > 10× 109/l fueron las variables asociadas a una SLT inferior, mientras que el sistema pronóstico IPSET-Thrombosis no aportó mayor información que la estratificación clásica de riesgo trombótico (AU)
Background and objective: Two prognostic models to predict overall survival and thrombosis-free survival have been proposed: International Prognostic Score for Essential Thrombocythemia (IPSET) and IPSET-Thrombosis, respectively, based on age, leukocytes count, history of previous thrombosis, the presence of cardiovascular risk factors and the JAK2 mutational status. The aim of the present study was to assess the clinical and biological characteristics at diagnosis and during evolution in essential thrombocythemia (ET) patients as well as the factors associated with survival and thrombosis and the usefulness of these new prognostic models. Patients and methods: We have evaluated the clinical data and the mutation status of JAK2, MPL and calreticulin of 214 ET patients diagnosed in a single center between 1985 and 2012, classified according to classical risk stratification, IPSET and IPSET-Thrombosis. Results: With a median follow-up of 6.9 years, overall survival was not associated with any variable by multivariate analysis. Thrombotic history and leukocytes > 10 × 109/l were associated with thrombosis-free survival (TFS). In our series, IPSET prognostic systems of survival and thrombosis did not provide more clinically relevant information regarding the classic risk of thrombosis stratification. Conclusion: Thrombotic history and leukocytosis > 10× 109/l were significantly associated with lower TFS, while the prognostic IPSET-Thrombosis system did not provide more information than classical thrombotic risk assessment (AU)
Subject(s)
Adult , Humans , Thrombocythemia, Essential/diagnosis , Thrombocythemia, Essential/mortality , Thrombocythemia, Essential/complications , Epidemiological Monitoring/trends , Thrombosis/diagnosis , Leukocytosis/diagnosis , Risk Factors , Prognosis , Spain/epidemiologyABSTRACT
OBJECTIVES: Clonal dominance is characteristic of patients with post-polycythemia vera myelofibrosis (post-PV MF), whereas patients in chronic phase usually display polyclonal hematopoiesis. The aim of this work was to study the mutational burden of JAK2V617F at the progenitor level in patients with PV and correlate it with the evolutive phase of the disease and the presence of mutations in genes different to JAK2V617F. METHODS: JAK2V617F was measured in stem cells, progenitor cells, and granulocytes of 45 patients with PV (early chronic phase n = 26, late chronic phase n = 10, post-PV MF n = 9). In addition, screening of TET2, DNMT3A, ASXL1, SF3B1, SRSF2, U2AF1, and TP53 was performed with quantification of the mutation in CD34+ cells in positive cases. Moreover, we assessed whether JAK2V617F allele burden in granulocytes (at a single time point or monitoring) could be used as a surrogate of clonal dominance. RESULTS: Ten patients presented clonal dominance at progenitor level (PV at diagnosis n = 2, late chronic phase n = 1, post-PV MF n = 7). Additional mutations were identified in four patients at diagnosis, three in TET2, and one in DNMT3A gene, with clonal dominance present in three of them. At PV diagnosis, clonal dominance was demonstrated only in patients with additional mutations. JAK2V617F monitoring showed better diagnostic accuracy than single time point measurement as a marker of clonal dominance. CONCLUSIONS: Clonal dominance may be present at diagnosis, especially in those cases carrying other mutations. JAK2V617F monitoring during follow-up could help in the identification of patients with clonal dominance.
Subject(s)
DNA (Cytosine-5-)-Methyltransferases/genetics , DNA-Binding Proteins/genetics , Hematopoietic Stem Cells/metabolism , Janus Kinase 2/genetics , Polycythemia Vera/genetics , Primary Myelofibrosis/genetics , Proto-Oncogene Proteins/genetics , Adult , Aged , Aged, 80 and over , Alleles , Clone Cells , DNA (Cytosine-5-)-Methyltransferases/metabolism , DNA Methyltransferase 3A , DNA-Binding Proteins/metabolism , Dioxygenases , Disease Progression , Female , Gene Expression , Granulocytes/metabolism , Granulocytes/pathology , Hematopoiesis/genetics , Hematopoietic Stem Cells/pathology , Humans , Janus Kinase 2/metabolism , Male , Middle Aged , Mutation , Polycythemia Vera/complications , Polycythemia Vera/diagnosis , Polycythemia Vera/pathology , Primary Myelofibrosis/diagnosis , Primary Myelofibrosis/etiology , Primary Myelofibrosis/pathology , Proto-Oncogene Proteins/metabolismABSTRACT
BACKGROUND AND OBJECTIVE: Two prognostic models to predict overall survival and thrombosis-free survival have been proposed: International Prognostic Score for Essential Thrombocythemia (IPSET) and IPSET-Thrombosis, respectively, based on age, leukocytes count, history of previous thrombosis, the presence of cardiovascular risk factors and the JAK2 mutational status. The aim of the present study was to assess the clinical and biological characteristics at diagnosis and during evolution in essential thrombocythemia (ET) patients as well as the factors associated with survival and thrombosis and the usefulness of these new prognostic models. PATIENTS AND METHODS: We have evaluated the clinical data and the mutation status of JAK2, MPL and calreticulin of 214 ET patients diagnosed in a single center between 1985 and 2012, classified according to classical risk stratification, IPSET and IPSET-Thrombosis. RESULTS: With a median follow-up of 6.9 years, overall survival was not associated with any variable by multivariate analysis. Thrombotic history and leukocytes>10×10(9)/l were associated with thrombosis-free survival (TFS). In our series, IPSET prognostic systems of survival and thrombosis did not provide more clinically relevant information regarding the classic risk of thrombosis stratification. CONCLUSION: Thrombotic history and leukocytosis>10×10(9)/l were significantly associated with lower TFS, while the prognostic IPSET-Thrombosis system did not provide more information than classical thrombotic risk assessment.
Subject(s)
Thrombocythemia, Essential/diagnosis , Adolescent , Adult , Aged , Aged, 80 and over , Child , Female , Follow-Up Studies , Humans , Incidence , Male , Middle Aged , Prognosis , Retrospective Studies , Risk Assessment , Risk Factors , Survival Analysis , Thrombocythemia, Essential/complications , Thrombocythemia, Essential/mortality , Thrombosis/epidemiology , Thrombosis/etiology , Young AdultABSTRACT
BACKGROUND AND OBJECTIVE: Atypical chronic myeloid leukemia (aCML) and chronic neutrophilic leukemia (CNL) display similar clinical and hematological characteristics. The objective of the present study was to determine the mutational status of SETBP1 and CSF3R in these diseases. PATIENTS AND METHOD: The mutational status of SETBP1 and CSF3R was studied in 7 patients with aCML (n = 3), CNL (n = 1) and unclassifiable myeloproliferative neoplasms (MPN-u) (n = 3). Additionally, mutations in ASXL1, SRSF2, IDH1/2, DNMT3A, and RUNX1 were also analyzed. RESULTS: SETBP1 mutations (G870S and G872R) were detected in 2 patients with MPN-u, and one of them also presented mutations in SRSF2 (P95H) and ASXL1 (E635fs). The CNL case showed mutations in CSFR3 (T618I), SETBP1 (G870S) and SRSF2 (P95H). No patient classified as aCML had mutations in SETBP1 or CSF3R. One of the patients with mutations evolved to acute myeloid leukemia, while the other 2 had disease progression without transformation to overt leukemia. CONCLUSION: The knowledge of the molecular alterations involved in these rare diseases is useful in the diagnosis and may have an impact on both prognosis and therapy.
Subject(s)
Carrier Proteins/genetics , Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative/genetics , Leukemia, Neutrophilic, Chronic/genetics , Mutation , Neoplasm Proteins/genetics , Nuclear Proteins/genetics , Receptors, Colony-Stimulating Factor/genetics , Aged , Aged, 80 and over , Core Binding Factor Alpha 2 Subunit/genetics , DNA Mutational Analysis , DNA, Neoplasm/genetics , Disease Progression , Fatal Outcome , Female , Humans , Leukemia, Myelomonocytic, Acute/genetics , Male , Middle Aged , Myeloproliferative Disorders/genetics , Prognosis , Repressor Proteins/genetics , Ribonucleoproteins/genetics , Serine-Arginine Splicing FactorsABSTRACT
Low serum erythropoietin (EPO) is a minor criterion of Polycythaemia Vera (PV) but its diagnostic usefulness relies on studies performed before the discovery of JAK2 V617F mutation. The objective of the present study was to evaluate the diagnostic accuracy of serum EPO and JAK2 V617F allele burden as markers of PV as well as the combination of different diagnostic criteria in 287 patients (99 with PV, 137 with Essential Thrombocythaemia and 51 with non-clonal erythrocytosis). Low EPO showed good diagnostic accuracy as a marker for PV, with the area under the curve (AUC) of the chemiluminescent-enhanced enzyme immunoassay (CEIA) being better than that of radioimmunoassay (RIA) (0·87 and 0·76 for CEIA and RIA, respectively). JAK2 V617F quantification displayed an excellent diagnostic accuracy, with an AUC of 0·95. A haematocrit >52% (males) or >48% (females) plus the presence of the JAK2 V617F mutation had a sensitivity and specificity of 79% and 97%, respectively. Adding low EPO or the JAK2 V617F allele burden did not improve the diagnostic accuracy for PV whereas the inclusion of both improved the sensitivity up to 83% and maintaining 96% specificity. Haematocrit and qualitative JAK2 V617F mutation allow a reliable diagnosis of PV. Incorporation of EPO and/or JAK2 V617F mutant load does not improve the diagnostic accuracy.
Subject(s)
Erythropoietin/blood , Janus Kinase 2/genetics , Mutation, Missense , Point Mutation , Polycythemia Vera/diagnosis , Alleles , Amino Acid Substitution , Area Under Curve , Biomarkers , Diagnosis, Differential , Female , Hematocrit , Hemoglobins/analysis , Humans , Leukocyte Count , Male , Platelet Count , Polycythemia/diagnosis , Polycythemia Vera/blood , Polycythemia Vera/genetics , ROC Curve , Reproducibility of Results , Sensitivity and Specificity , Thrombocythemia, Essential/diagnosisABSTRACT
Therapeutic options for patients with polycythemia vera (PV) and essential thrombocythemia (ET) resistant or intolerant to hydroxyurea are limited. Busulfan is effective as first-line therapy, but there is scarce information on this drug as second-line treatment. The efficacy of busulfan in patients with advanced PV or ET refractory or intolerant to hydroxyurea was assessed in 36 patients (PV n = 15, ET n = 21) treated for a median of 256 days. Complete hematological response (CHR) was achieved in 83 % of patients, after a median time of 203 days (range 92-313). The probability of sustained CHR at 1 and 2 years was 87 and 62 %, respectively. Time to CHR was shorter in patients treated with ≥14 mg of busulfan per week than with lower doses (141 versus 336 days, p = 0.01). Partial molecular response was achieved in three out of nine (33 %) patients. Busulfan was stopped in 27 patients (75 %) due to CHR achievement in 18 cases (67 %), hematological toxicity in 8 cases (30 %), and disease transformation in 1 case. With a median follow-up of 721 days, six patients have died, with the probability of survival at 2 years being 85 %. The probability of thrombosis at 2 years was 11 %. Transformation into acute leukemia or myelodysplastic syndrome was observed in three cases, all of them in a JAK2V617F-negative clone carrying additional mutations. Busulfan, at a dose of 2 mg/day, is an effective option for elderly patients with PV or ET who fail to hydroxyurea, but a significant rate of transformation was observed.
Subject(s)
Alkylating Agents/therapeutic use , Busulfan/therapeutic use , Polycythemia Vera/drug therapy , Thrombocythemia, Essential/drug therapy , Aged , Aged, 80 and over , Blood Cell Count , Comorbidity , Disease Progression , Drug Resistance , Drug Substitution , Female , Hematocrit , Hemorrhage/etiology , Humans , Hydroxyurea/adverse effects , Hydroxyurea/therapeutic use , Janus Kinase 2/genetics , Kaplan-Meier Estimate , Leukemia, Myeloid, Acute/epidemiology , Leukemia, Myeloid, Acute/etiology , Male , Middle Aged , Polycythemia Vera/complications , Polycythemia Vera/genetics , Remission Induction , Risk Factors , Thrombocythemia, Essential/complications , Thrombocythemia, Essential/genetics , Thrombosis/etiology , Treatment OutcomeABSTRACT
Bone marrow histology is included in the diagnostic criteria of myeloproliferative neoplasms (MPNs). However, some concerns have emerged about its reproducibility. To evaluate the diagnostic accuracy of histology and to assess its correlation with presence of mutations and clinical outcomes, two pathologists reviewed the bone marrow biopsies corresponding to 211 patients with MPN. Despite the low agreement in the evaluation of individual histopathological characteristics, the concordance among pathologists when establishing the diagnosis was good (Kappa index 0·67). The specificity of histology was 100%, 98·5% and 98% in polycythaemia vera (PV), essential thrombocythaemia (ET) and primary myelofibrosis (PMF), respectively, whereas the sensitivity of histological diagnosis was low in PV and ET (32·5% and 54% respectively) and acceptable in PMF (75%). Thirteen out of 146 (9%) patients with clinical ET were diagnosed as prefibrotic PMF. No histological agreement or MPN otherwise unspecified was more frequently observed in JAK2 V617F-positive ET than in CALR-mutated cases, whereas megakaryocytic abnormalities and prefibrotic PMF were more frequently observed in CALR-mutated ET. In conclusion, histological criteria of MPN have a limited diagnostic accuracy due to low sensitivity. Patients with JAK2 V617F-positive MPN have a heterogeneous histology while CALR-positive ET is associated with megakaryocyte abnormalities and prefibrotic PMF.
Subject(s)
Bone Marrow/pathology , Mutation/genetics , Myeloproliferative Disorders/pathology , Adult , Aged , Biopsy , Calreticulin/genetics , Female , Humans , Janus Kinase 2/genetics , Male , Middle Aged , Myeloproliferative Disorders/genetics , Observer Variation , Prognosis , Receptors, Thrombopoietin/geneticsSubject(s)
Adenocarcinoma/genetics , Antineoplastic Agents/therapeutic use , ErbB Receptors/genetics , Lung Neoplasms/genetics , Quinazolines/therapeutic use , Adenocarcinoma/drug therapy , Aged, 80 and over , Exons/genetics , Female , Gefitinib , Humans , INDEL Mutation , Lung Neoplasms/drug therapyABSTRACT
The JAK2V617F allele burden has been identified as a risk factor for vascular events and myelofibrotic transformation in polycythemia vera (PV) and essential thrombocythemia (ET). However, all previous studies have evaluated a single time point JAK2V617F measurement. Therefore, the frequency and the clinical significance of changes in the JAK2V617F mutant load occurring during the disease evolution remain unknown. In the present study, JAK2V617F monitoring was performed during the follow-up of 347 patients (PV = 163, ET = 184). According to their JAK2V617F evolutionary patterns, patients were stratified as stable < 50% (n = 261), stable ≥50% (n = 52), progressive increase (n = 24) and unexplained decrease (n = 10). After a 2,453 person-years follow-up, a total of 59 thrombotic events, 16 major hemorrhages, and 27 cases of myelofibrotic transformations were registered. At multivariate analyses, patients with a persistently high (≥50%) or unsteady JAK2V617F load during follow-up had an increased risk of myelofibrotic transformation (Incidence rate ratio [IRR]: 20.7, 95% CI: 6.5-65.4; P < 0.001) and a trend for a higher incidence of thrombosis (IRR: 1.7, 1-3.3; P = 0.05) than patients with a stable allele burden below 50%. In conclusion, JAK2V617F monitoring could be useful in patients with PV and ET for predicting disease's complications, especially myelofibrotic transformation.
Subject(s)
Janus Kinase 2/blood , Janus Kinase 2/genetics , Polycythemia Vera/enzymology , Primary Myelofibrosis/enzymology , Thrombocythemia, Essential/enzymology , Thrombosis/enzymology , Adult , Aged , Aged, 80 and over , Alleles , Female , Humans , Incidence , Male , Middle Aged , Polycythemia Vera/blood , Polycythemia Vera/genetics , Primary Myelofibrosis/blood , Primary Myelofibrosis/genetics , Survival Analysis , Thrombocythemia, Essential/blood , Thrombocythemia, Essential/genetics , Thrombosis/blood , Thrombosis/genetics , Young AdultSubject(s)
Mutation , Polycythemia Vera/genetics , RNA Splicing , Thrombocythemia, Essential/genetics , HumansABSTRACT
We have characterized the molecular changes underlying the transformation of a JAK2V617F+-myelofibrosis with trisomy 8, into a JAK2V617F-negative leukemia. Leukemic clone did not carry JAK2V617F mutation, but showed ASXL1 mutation (R693X). This mutation was identified in a low percentage at diagnosis by next-generation sequencing. Using this technology in serial specimens during the follow-up, we observed a progressive expansion of the ASXL1-mutated minor clone, whereas the JAK2V617F+-clone carrying trisomy 8 decreased. Hematologic progression occurred simultaneously with an ASXL1-R693X-negative lung-cancer. This is the first report showing a clear association between the expansion of an ASXL1-mutated clone and the leukemic transformation of myelofibrosis.
Subject(s)
Cell Transformation, Neoplastic , Janus Kinase 2/genetics , Leukemia, Myeloid, Acute/genetics , Mutation , Primary Myelofibrosis/genetics , Repressor Proteins/genetics , Chromosomes, Human, Pair 8 , Humans , Janus Kinase 2/metabolism , Leukemia, Myeloid, Acute/pathology , Male , Middle Aged , Primary Myelofibrosis/enzymology , Primary Myelofibrosis/metabolism , Primary Myelofibrosis/pathology , Repressor Proteins/metabolism , Trisomy/geneticsABSTRACT
JAK2V617F allele burden was prospectively measured in polycythemia vera (PV, n=52) and essential thrombocythemia (ET, n=39) patients receiving hydroxycarbamide (HC) and analyzed according to JAK2 46/1 haplotype and genotype of SLC14A1, SLC14A2 and ARG2 urea transporters. Molecular response (MR) was obtained in 68.7% and 38.9% of PV patients with GG and AA or GA genotype in SLC14A2, respectively (p=0.07). No significant differences were observed neither in PV nor in ET according to JAK2 46/1 haplotype, SLC14A1 and ARG2. In conclusion, JAK2 46/1 haplotype does not influence MR in HC treated patients and urea transporters polymorphisms display a minimal effect.
Subject(s)
Genetic Predisposition to Disease , Hydroxyurea/therapeutic use , Janus Kinase 2/genetics , Mutation , Myeloproliferative Disorders/drug therapy , Myeloproliferative Disorders/genetics , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/therapeutic use , Arginase/genetics , Female , Gene Frequency , Genotype , Haplotypes , Humans , Male , Membrane Transport Proteins , Middle Aged , Outcome Assessment, Health Care , Polycythemia Vera/drug therapy , Polycythemia Vera/genetics , Prospective Studies , Thrombocythemia, Essential/drug therapy , Thrombocythemia, Essential/genetics , Urea TransportersSubject(s)
Adenocarcinoma/drug therapy , ErbB Receptors/genetics , Exons/genetics , Lung Neoplasms/drug therapy , Mutation/genetics , Protein Kinase Inhibitors/therapeutic use , Quinazolines/therapeutic use , Adenocarcinoma/pathology , Aged, 80 and over , ErbB Receptors/antagonists & inhibitors , Gefitinib , Humans , Lung Neoplasms/pathology , Male , Middle Aged , Tomography, X-Ray Computed , Treatment OutcomeABSTRACT
The cut off for hemoglobin or hematocrit that indicates the need for an isotopic red cell mass study was investigated in 179 patients with a presumptive diagnosis of polycythemia vera or essential thrombocythemia. Hematocrit showed better diagnostic accuracy than hemoglobin. Hemoglobin over 18.5 g/dL in males or over 16.5 g/dL in females showed a high specificity indicating that red cell mass study could be avoided in such cases, but it showed low sensitivity leading to 46% false negatives. The best value of hematocrit to indicate a red cell mass study was 0.50 L/L in males (specificity 75%, sensitivity 87.5%) and 0.48 L/L in females (specificity 73%, sensitivity 94%). Lowering the hematocrit threshold to 0.48 L/L in males increased sensitivity up to 95%. A red cell mass study should be performed in patients with suspected diagnosis of essential thrombocythemia or polycythemia vera and with hematocrit between 0.48 L/L and 0.52 L/L.
Subject(s)
Erythrocyte Volume , Hemoglobins/analysis , Polycythemia Vera/blood , Thrombocytopenia/blood , Adult , Aged , Aged, 80 and over , Female , Hematocrit , Hemoglobins/metabolism , Humans , Male , Middle Aged , Polycythemia Vera/diagnosis , Retrospective Studies , Sex Factors , Thrombocytopenia/diagnosisABSTRACT
JAK2V617F-negative essential thrombocythemia (ET) is a heterogeneous disease including clonal cases and others without evidence of clonality. However, it is unknown if the detection of myeloid clonality in JAK2V617F-negative ET patients confers a different clinical outcome than those in whom clonal hematopoiesis cannot be demonstrated. The objective of the present study was to evaluate the clinical significance of clonality assessment in patients with JAK2V617F-negative ET. Clonality investigation including mutational status of MPL, TET2, and ASXL1 genes and human androgen receptor (HUMARA) assay was performed in 73 JAK2V617F-negative cases out of 186 subjects consecutively diagnosed with ET in a single institution, at diagnosis or during follow-up. Mutations in MPL, TET2, and ASXL1 were observed in 7, 4, and 2 cases, respectively, whereas clonality by HUMARA assay was demonstrated in 21 out of 46 (46 %) female patients. With a median follow-up of 8 years, death, thrombosis, bleeding, and disease transformation were registered in 7, 10, 8, and 6 patients, respectively. No differences in thrombosis, bleeding or survival were observed according to clonality assessment. The probability of disease transformation at 10 years was higher in patients showing clonal hematopoiesis by presenting mutations in either MPL, TET2, or ASXL1 (64 versus 2 % in patients without mutations, p < 0.001) and in those with HUMARA clonality (35 versus 0 % in patients with polyclonal hematopoiesis, p < 0.004). In conclusion, disease transformation is associated with evidence of clonality in JAK2V617F-negative ET.
Subject(s)
Janus Kinase 2/genetics , Mutation/genetics , Thrombocythemia, Essential/diagnosis , Thrombocythemia, Essential/pathology , Adolescent , Adult , Aged , Aged, 80 and over , Child , Clone Cells , Cohort Studies , Female , Follow-Up Studies , Humans , Male , Middle Aged , Phenylalanine/genetics , Thrombocythemia, Essential/genetics , Valine/genetics , Young AdultABSTRACT
Mutations in the TET2 and ASXL1 genes have been described in approximately 14% and 8% of patients, respectively, with classic myeloproliferative neoplasms (MPN), but their role as possible new diagnostic molecular markers is still inconclusive. In addition, other genes such as IDH1, IDH2, and c-CBL have also been reported in several myeloid neoplasms. We have studied the mutational status of TET2 (complete coding region), ASXL1 (exon12), IDH1 (R132), IDH2 (R140 and R172), and c-CBL (exons 8 and 9) in 62 MPN patients (52 essential thrombocythemia (ET), five polycythemia vera (PV), and five primary myelofibrosis (PMF)) negative for both JAK2 (V617F and exon 12) and MPL (exon 10) mutations. Pathogenic alterations in the TET2 gene were detected in three out 52 ET cases (4.8%). ASXL1 gene pathogenic mutations were also detected in three cases (two ET and one PMF). One ET patient harbored, simultaneously, one TET2 and one ASXL1 mutations. Mutations in the TET2 and ASXL1 genes showed no association with the JAK2 46/1 haplotype. Analysis of a JAK2V617F-positive cohort of 50 ET patients showed no mutations in either the TET2 or ASXL1 genes. Regarding IDH1, IDH2, and c-CBL genes, no mutations were found in any patient. In conclusion, TET2 and ASXL1 pathogenic mutations are found in 8% of MPN lacking JAK2 and MPL mutations, whereas IDH1, IDH2, and c-CBL mutations are not detected in this subset of patients.
Subject(s)
DNA-Binding Proteins/genetics , Isocitrate Dehydrogenase/genetics , Janus Kinase 2/genetics , Myeloproliferative Disorders/genetics , Proto-Oncogene Proteins c-cbl/genetics , Proto-Oncogene Proteins/genetics , Receptors, Thrombopoietin/genetics , Repressor Proteins/genetics , Adult , Aged , Aged, 80 and over , Base Sequence , Cohort Studies , DNA Mutational Analysis , DNA-Binding Proteins/metabolism , Dioxygenases , Exons , Female , Genotype , Haplotypes , Humans , Isocitrate Dehydrogenase/metabolism , Janus Kinase 2/metabolism , Male , Middle Aged , Molecular Sequence Data , Mutation , Myeloproliferative Disorders/pathology , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-cbl/metabolism , Receptors, Thrombopoietin/metabolism , Repressor Proteins/metabolismABSTRACT
JAK2V617F allele burden was prospectively measured in untreated patients with polycythaemia vera (PV, n=26) or essential thrombocythaemia (ET, n=36) and compared according to JAK2 46/1 haplotype status. The mean increase in JAK2V617F allele burden per year was 1%, 0.8% and 6% for PV patients with the JAK2 46/1 haplotype in negative, heterozygous and homozygous status, respectively (p<0.001). The JAK2 46/1 haplotype had no influence in JAK2V617 allele burden in ET. In conclusion, untreated PV patients homozygous for the JAK2 46/1 haplotype show a progressive increase in the JAK2V617F allele burden during the evolution of the disease.
