JAK2, CALR, and MPL Mutation Profiles in Colombian patients with BCR-ABL Negative Myeloproliferative Neoplasms

Background: Among the chronic myeloproliferative neoplasms (MPNs) not associated with BCR-ABL mutations are polycythemia vera, primary myelofibrosis, and essential thrombocythemia. These diseases are caused by mutations in genes, such as the JAK2, MPL, and CALR genes, which participate in regulating the JAK-STAT signaling pathway. Objective: This study aimed to establish the frequencies of mutations in the JAK2, MPL, and CALR genes in a group of Colombian patients with a negative clinical diagnosis of BCR-ABL chronic myeloproliferative neoplasms. Methods: The JAK2 V617F and MPL W515K mutations and deletions or insertions in exon 9 of the CALR gene were analyzed in 52 Colombian patients with polycythemia vera, primary myelofibrosis, and essential thrombocythemia. Results: The JAK2V617F mutation was carried by 51.9% of the patients, the CALR mutation by 23%, and the MPL mutation by 3.8%; 23% were triple-negative for the mutations analyzed. In these neoplasms, 6 mutation types in CALR were identified, one of which has not been previously reported. Additionally, one patient presented a double mutation in both the CALR and JAK2 genes. Regarding the hematological results for the mutations, significant differences were found in the hemoglobin level, hematocrit level, and platelet count among the three neoplasms. Conclusion: Thus, this study demonstrates the importance of the molecular characterization of the JAK2, CALR and MPL mutations in Colombian patients (the genetic context of which remains unclear in the abovementioned neoplasms) to achieve an accurate diagnosis, a good prognosis, adequate management, and patient survival.

Antecedentes: Entre las neoplasias mieloproliferativas crónicas no asociadas con mutaciones BCR-ABL se encuentran la policitemia vera, la mielofibrosis primaria y la trombocitemia esencial. Estas enfermedades están causadas por mutaciones en genes, como los genes JAK2, MPL y CALR, que participan en la regulación de la vía de señalización JAK-STAT. Objetivo: Establecer las frecuencias de mutaciones en los genes JAK2, MPL y CALR en un grupo de pacientes colombianos con diagnóstico clínico negativo de NMP BCR-ABL. Metodos: Se analizaron las mutaciones y deleciones o inserciones JAK2 V617F y MPL W515K en el exón 9 del gen CALR en 52 pacientes colombianos con policitemia vera, mielofibrosis primaria y trombocitemia esencial. Resultados: La mutación JAK2V617F la portaban el 51.9% de los pacientes, la mutación CALR el 23.0% y la mutación MPL el 3.8%; El 23.0% fueron triple negativos para las mutaciones analizadas. En estas neoplasias se identificaron seis tipos de mutación en CALR, uno de los cuales no ha sido reportado previamente. Además, un paciente presentó una doble mutación tanto en el gen CALR como en el JAK2. En cuanto a los resultados hematológicos para las mutaciones, se encontraron diferencias significativas en el nivel de hemoglobina, el nivel de hematocrito y el recuento de plaquetas entre las tres neoplasias. Conclusiones: Así, este estudio demuestra la importancia de la caracterización molecular de las mutaciones JAK2, CALR y MPL en pacientes colombianos (cuyo contexto genético aún no está claro en las neoplasias antes mencionadas) para lograr un diagnóstico certero, un buen pronóstico, un manejo adecuado y una mejoría del paciente. supervivencia.

Transient leukaemia of Down syndrome in a neonate: case report

Transient leukemia of Down syndrome(TL-DS)' or transient myeloproliferative disorder (TMD) or transient abnormal myelopoiesis (TAM) is a hematologic abnormality characterized by an uncontrolled proliferation of myeloblasts in peripheral blood and bone marrow which characteristically affects newborns and babies with Down syndrome. Children with Down syndrome (Trisomy 21) have a unique predisposition to develop myeloid leukemia of Down syndrome(ML-DS). In majority of cases of TL-DS, the GATA1 mutant clone goes into spontaneous remission without the need for chemotherapy. However, 10-20 % of neonates with TL-DS and silent TL-DS subsequently develop ML-DS in the first 5 years of life due to additional oncogenic mutations acquired by the persistent GATA1 mutant cells. We present here, one such case of Down syndrome with TL-DS in a neonate.

A Case of Transient Myeloproliferative Disorder Associated with Clonal Trisomy 21 in a Chromosomally Normal Newborn / 임상소아혈액종양

Transient myeloproliferative disorder (TMD) is similar to congenital leukemia, with leukocytosis, increased peripheral blast cells, and hepatomegaly in the neonatal period. Although TMD occurs only in patients with Down syndrome and trisomy 21 mosaicism, there have been reports of congenital leukemia with trisomy 21 limited to hematopoietic cells showing spontaneous resolution. We identified trisomy 21 in the leukemic cells in a patient with congenital leukemia. As there was no other gene abnormality, we stopped chemotherapy, and the disease resolved spontaneously. We reviewed the cases of clonal trisomy 21 TMD and found that their clinical features were similar to those of TDM associated with Down syndrome. In conclusion, in a phenotypically normal patient with suspected congenital leukemia, it is necessary to confirm the presence of 21 trisomy. If the neonate has only trisomy 21 without other gene abnormalities, intensive chemotherapy may not be required.

Differences in Clinical Characteristics of Transient Myeloproliferative Disease and Leukemia in Down Syndrome: A Single University Hospital Study / 임상소아혈액종양

BACKGROUND: Children with Down syndrome (DS) have a 10- to 20-fold increased risk of developing leukemia. However, in some patients, leukemia does not become apparent despite significant number of blast cells in the peripheral blood. This condition is called Transient myeloproliferative disorder (TMD), and is a disease entity unique to DS newborns and defined as the morphologic detection of blasts in DS less than three months of age. The present study investigated whether there was a difference between leukemia and TMD, and determined prognostic and risk factors. METHODS: We collected blood samples from 317 patients of 433 DS confirmed patients. We found 18 patients who had blast cells in their peripheral blood. RESULTS: Twelve patients were positive for blasts during the neonate period, and only one patient progressed to leukemia. The other 11 patients were later diagnosed with TMD. Six more patients were later diagnosed with leukemia, therefore, 7 patients were diagnosed with leukemia in total. All patients diagnosed with leukemia had anemia at the time of diagnosis, which was not found in TMD patients. All leukemia patients developed their disease after three months of life. Acute Myeloid Leukemia (AML) patients had additional chromosome mutation to trisomy 21 when they were diagnosed. CONCLUSION: In patients with Down Syndrome, anemia at diagnosis and age of onset could be helpful in distinguishing TMD from acute leukemia. Cancerous mutations in the chromosomes of peripheral and marrow blast cells of Down syndrome patients may foreshadow acute leukemia.

A Case of Myeloid Neoplasm with a PDGFRB Rearrangement and Eosinophilia / 대한내과학회지

Myeloid neoplasia with eosinophilia and platelet-derived growth factor receptor beta (PDGFRB) rearrangements is an uncommon Philadelphia-negative myeloproliferative neoplasm. Their most common morphological diagnosis is chronic myelomonocytic leukemia with eosinophilia, which is associated with t(5;12)(q33;p13) and results in the formation of the ETV6-PDGFRB fusion gene. Here, we report a 49-year-old man with a myeloid neoplasm with a PDGFRB rearrangement, who was incidentally diagnosed with hyperleukocytosis and eosinophilia during a health screening. A chromosome analysis of a bone marrow sample revealed 46, XY, t(5;12)(q33;p13), and fluorescence in situ hybridization analysis revealed the PDGFRB gene rearrangement. The patient was treated with imatinib and subsequently achieved complete hematological and molecular remission.

Differences in Clinical Characteristics of Transient Myeloproliferative Disease and Leukemia in Down Syndrome: A Single University Hospital Study / 임상소아혈액종양

BACKGROUND: Children with Down syndrome (DS) have a 10- to 20-fold increased risk of developing leukemia. However, in some patients, leukemia does not become apparent despite significant number of blast cells in the peripheral blood. This condition is called Transient myeloproliferative disorder (TMD), and is a disease entity unique to DS newborns and defined as the morphologic detection of blasts in DS less than three months of age. The present study investigated whether there was a difference between leukemia and TMD, and determined prognostic and risk factors.METHODS: We collected blood samples from 317 patients of 433 DS confirmed patients. We found 18 patients who had blast cells in their peripheral blood.RESULTS: Twelve patients were positive for blasts during the neonate period, and only one patient progressed to leukemia. The other 11 patients were later diagnosed with TMD. Six more patients were later diagnosed with leukemia, therefore, 7 patients were diagnosed with leukemia in total. All patients diagnosed with leukemia had anemia at the time of diagnosis, which was not found in TMD patients. All leukemia patients developed their disease after three months of life. Acute Myeloid Leukemia (AML) patients had additional chromosome mutation to trisomy 21 when they were diagnosed.CONCLUSION: In patients with Down Syndrome, anemia at diagnosis and age of onset could be helpful in distinguishing TMD from acute leukemia. Cancerous mutations in the chromosomes of peripheral and marrow blast cells of Down syndrome patients may foreshadow acute leukemia.

Prevalence of JAK2V617F mutation in intra-abdominal venous thrombosis.

Background and aim: Myeloproliferative disorders (MPD) (like polycythemia vera, essential thrombocythemia and primary myelofibrosis) are responsible for 50% cases of Budd-Chiari syndrome (BCS) and 35% cases of portal venous thrombosis (PVT) in western series. A point mutation at Val617Phe of Janus kinase 2 tyrosine kinase gene (JAK2V617F mutation) occurs in high proportion with MPD. This may be useful in diagnosing overt and latent form of MPD in intra-abdominal venous thrombosis (IAVT), consisting of BCS and PVT. Methods: In a 4 year prospective study from 2006 to 2009, JAK2 mutations were assessed in all patients diagnosed with MPD and IAVT attending our institution. Twenty three healthy individuals and 31 patients with non-MPD hematological disorders served as controls. All patients of idiopathic IAVT were tested for the mutation. Test for JAK2V617F mutation was carried out by allele specific polymerase chain reaction. Results: JAK2 V617F mutation was significantly more common in MPD patients (76%) than in non-MPD hematological disorders (0%) and healthy controls (0%). There was no statistical difference in presence of JAK2V617F mutation in patients of MPD with or without thrombosis (80% vs. 74%). In 58 patients with IAVT, the JAK2V617F mutation was present in 40%with BCS, 14% with PVT and 100% combined BCS+PVT). Conclusions: The JAK2V617F mutation occurs at high frequency in patients with MPD and IAVT. All idiopathic IAVT patients must be screened for JAK2V617F mutation to detect latent MPD. Detection of latent MPD by JAK2V617F mutation in BCS may change treatment strategy and outcome.

A Case of Atypical Chronic Myeloid Leukemia with the JAK2V617F Mutation

Atypical chronic myeloid leukemia (aCML) is a rare leukemic disorder that shows myelodysplastic and myeloproliferative features simultaneously. The Janus kinase 2 gene V617F mutation (JAK2V617F) in aCML has been the source of much controversy. Some JAK2V617F positive cases have been reported but others observed no JAK2V617F mutation in aCML as defined by WHO classification. Recently, we experienced a case of aCML with JAK2V617F mutation with typical myelodysplastic/myeloproliferative features in peripheral blood and bone marrow aspirates. The karyotype was normal and no BCR/ABL1, PDGFRA or PDGFRB gene rearrangement was noted with FISH analysis. JAK2V617F mutation of the case was identified with amplification refractory mutation system PCR and direct sequencing. We also studied JAK2V617F mutation status in 3 additional cases of previously diagnosed aCML in our institution, but no mutation was identified.

A Case of Pulmonary Thromboembolism with JAK2 Mutation / 결핵및호흡기질환

The incidence of pulmonary thromboembolism increases with age. The risk factors of pulmonary thromboembolism include surgery, malignancy, obesity, lupus anticoagulants, and vascular conditions such as deep vein thrombosis. Thromboembolism in younger patients or in unusual locations, the possibility of primary thrombophilic conditions should be considered. Primary thrombophilic states include myeloproliferative disorders (MPD). JAK2 V617F mutation is found commonly in patients diagnosed with MPD, in 90~95% of polycythemia vera (PV) and in 50~60% of essential thrombocytosis (ET) patients. Sometimes the JAK2 V617F mutation is found in cases without MPD. The relationship between JAK2 V617F mutation and thrombosis has not been defined. Recently, clinical evidence suggests that this mutation may be variably associated with thrombosis. We present one case of pulmonary thromboembolism in a young patient, who was positive for the JAK2 V617F mutation and did not have MPD.

Sarcoma granulocítico com apresentação inicial cutânea e ganglionar: [carta ao editor] / Granulocytic sarcoma of skin and lymph nodes: [letter to the editor]

A case of granulocytic sarcoma of skin and lymph nodes is reported in a 65-year-old man as an initial presentation of a myeloproliferative disorder, chiefly involving myelofibrosis. The symptoms, physical examination, hematological findings, imunohistochemistry and anatomopathological results and evolution of the disease are described. As this is an unusual case, stress was placed on the diagnostic confusion that may occur.

GATA1 Mutation in Transient Myeloproliferative Disorder of Down Syndrome

Children with Down syndrome (DS) have a higher risk of developing leukemia than do healthy children, and they especially have a higher risk for developing transient myeloproliferative disorder (TMD) or acute megakaryocytic leukemia (AMKL). In recent studies, it has been reported that most of these patients have acquired mutation of the GATA1 gene, which encodes the erythroid/megakaryocytic transcription factor GATA1. GATA1 mutations have not been found in AMKL patients who did not have DS and other hematologic malignancies in DS. Most of the GATA1 mutations in DS-TMD/AMKL are nonsense mutations that are mainly located in exon 2. We observed a nonsense mutation in exon 2 of GATA1 [c.189_190delCA (Tyr63X)] in one case of DS-TMD. The GATA1 mutation has been thought to be an early event in the leukemogenesis of DS-TMD/AMKL and it could be used as a stable molecular marker to assess the treatment response or to monitor for the recurrence of DS-TMD/AMKL.

A case of chronic neutrophilic leukemia / 대한내과학회지

Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative disorder characterized by clonal proliferation of mature neutrophils, hepatosplenomegaly, elevated leukocyte alkaline phosphatase score (ALP score) and a negative Philadelphia chromosome. To date, approximately 150 cases have been reported in the literature, including some cases presenting with a 'leukemic' state reflected by a neutrophilic reaction. The term 'true' CNL, recently introduced by Reilly, highlights the need for more experience with CNL cases to improve the diagnostic criteria. In Korea, about 10 cases have been reported in the literature and some of those cases did not meet the WHO diagnostic criteria for CNL. We present a typical case of CNL in a 66-year-old man who complained of general weakness and weight loss. On admission, the white blood cell count from the peripheral blood was 175,600/L with 80% segmented neutrophils. The cytogenic study was negative for the Philadelphia chromosome and had a normal karyotype.

Erythrophagocytosis by Myeloid Cells in a Patient with Myeloproliferative Disorder

This report documents a case of myeloid erythrophagocytosis in a patient with myeloproliferative disorder. The patient had pancytopenia and his marrow was hyperplastic with erythrophagocytosis by myeloid cells of various stages, including myeloblasts. He was diagnosed to have a prefibrotic stage of chronic idiopathic myelofibrosis. The erythrophagocytosis by myeloid cells persisted even after 2 months of treatment for the primary disorder.

A Case of POEMS Syndrome with Unclassifiable Myeloproliferative Disorder / 대한혈액학회지

POEMS syndrome is a rare multisystemic syndrome characterized by polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes. We report a case of POEMS syndrome associated with unclassifiable myeloproliferative disorder presenting with polyneuropathy, hepatosplenomegaly, hypothyroidism, hyperprolactinemia, monoclonal gammopathy, hyperpigmentation, hypertrichosis, ascites, peripheral edema, and pulmonary hypertension.

A Case of Transient Myeloproliferative Disorder with Down Syndrome, Presented Hepatosplenomegaly on Prenatal Sonography

Down syndrome (DS) is associated with a higher incidence of leukemia than general population; the subtype is acute megakaryoblastic leukemia (AMKL) in 50% of cases. DS is also strongly associated with transient myeloproliferative disorder (TMD), which is usually diagnosed during newborns and infants. Due to its difficulty in distinguishing TMD from acute leukemia (AL), the diagnosis of TMD should be made with extreme caution. Unlike AL, most cases of TMD resolve spontaneously within 3 months; blast cells disappear within 8 weeks in 80% and within 10 weeks in 90% of the surviving patients. Some infants with TMD, however, may have a severe complication leading into life-threatening clinical course with hepatosplenomegaly, lymphadenopathy, liver impairment, respiratory distress, anemia, infection and hemorrhage. Rarely, AL can develop after remission of TMD. We report a case of TMD with DS in newly born infant who presented hepatosplenomegaly on prenatal sonography and improved with exchange transfusion, steroid.

Down Syndrome with Transient Myeloproliferative Disorder, Hepatic Fibrosis, and Hemochromatosis

Transient myeloproliferative disorder (TMD), which may mimic acute leukemia, occurs in neonates with Down syndrome along with hepatic fibrosis. TMD is recognized shortly after birth or in the neonatal period and is characterized by leukocytosis and thrombocytopenia, which resolve spontaneously in four to six weeks. And hepatic fibrosis is characterized by diffuse intralobular sinusoidal fibrosis, extramedullary hematopoiesis and hemochromatosis. A newborn male infant with Down syndrome, atrial septal defect and ventricular septal defect is reported. He showed abnormal myelopoiesis accompanying characteristic hepatic sinusoidal fibrosis. Knowing the cellular mechanism of hepatic fibrosis and its modulation by growth factors, a pathogenetic link between transient myeloproliferative disorder and the development of liver fibrosis in Down syndrome neonates, association of this triad no longer appears to be accidental.

Essential thrombocythemia.

A review of twelve cases of Essential Thrombocythemia at Suratthani Hospital, aged between 48 to 87 years old, 6 male and 6 female. The initial clinical presentations were as follows: 2 asymptomatic cases (incidentally found on routine CBC check up), 4 cases of cerebral infarction (one of them presented with paresthesia, erythromelalgia, transient ischemic attack, and a convulsion which finally progressed to cerebral infarction), 1 case with ischemic heart disease, 1 case with deep vein thrombosis of the left leg and an intramuscular hematoma of the left calf,1 case with an intramuscular hematoma of the right gluteus muscle,1 case with ischemic gangrene of the toes and an upper gastrointestinal hemorrhage, 1 case with erythromelagia with an ischemic digital ulcer and another case with a post-operative hematoma. The average platelet count was 1,524x103/ตl. The treatment regimens were Busulfan or Hydroxyurea and additional treatment with an antiplatelet aggregation agent in patients with vascular occlusive disease. The patients responded well to the treatment. Due to the long natural history of essential thrombocythemia and the leukemogenic side effects of chemotherapy, more suitable therapy is considered especially in asymptomatic patients.

Clinical and hematological study of myelodysplastic syndrome / 中国综合临床

Objective To study the clinical characteristics,diagnosis and differential diagnosis of myelodysplastic syndrome.Methods The clinical features,routine hematological tests and morphology of medullary cells were analyzed in 49 cases.Results Of 49 cases,there were 36.7% of RA,8.2% of RAS,20.4% of RAEB,30.6% of RAEBT and 4.0% of CMML,respectively ,which showed the positive pathosis hemogenesis ,and had a trend of transforming to leukemia.Conclusion MDS(especially RA)is difficult to diagnose,which should be diagnosed according to pathosis hemogensis.The detection of blasts in peripheral blood will help to differentiate RA and CAA,but more researches should be made on the differentiation of MDS/AML and AML TMDS.

Transient Myeloproliferative Disorder with Mosaic Down Syndrome: A Case Report / 대한혈액학회지

Individuals with Down syndrome have a high incidence of hematologic diseases such as transient myeloproliferative disorder (TMD) and acute leukemia comparing to the normal children. TMD usually undergoes complete recovery within a few months without any treatment. In Korea, there were several cases of TMD with Down syndrome in the literatures, but no reports of TMD in a phenotypically normal newborn with mosaic Down syndrome. We experienced a case of TMD in a 19- day-old male who was phenotypically normal newborn with mosaic Down syndrome. Specific treatment was withheld, hematologic recovery occurred within one month of diagnosis. We report the case with brief review of literature.

Pattern of Von Willebrand Factor Antigen and Large Von Willebrand Factor Multimer in Myeloproliferative Disorder and Reactive Thrombocytosis / 대한혈액학회지

BACKGROUND: Von Willebrand factor (vWf) plays a crucial role in the early phase of hemostasis. Acquired von Willebrand disease (vWD) due to abnormalities of vWf multimers has been reported in patients with myeloproliferative disorders (MPD) who have high platelet counts. We compared the distribution of plasma vWf antigen and large vWf multimers in samples obtained from patients with MPD and reactive thrombocytosis (RT). Furthermore, we tried to find the relationship between the decrease of large vWf multimers in plasma and the bleeding complication. METHODS: Sixteen patients with MPD and twenty-five patients with RT with more than 600x103/microliter of platelets were included in the study. The numbers of platelets and leukocytes, platelet distribution width (PDW), mean platelet volume (MPV), platelet-large cell ratio (P-LCR), vWf : Ag and vWf multimers were measured. RESULTS: The mean values of platelets and leukocytes were 1,091x103/microliter, 82.9x103/ in MPD and 763x103/, 11.4x103/ in RT (P<0.05). Platelet parameters such as MPV,PDW, P-LCR were 11.2 fL, 10.2%, 28.6% in MPD, and 9.6 fL, 9.9%, 19.6% in RT (P<0.05). The levels of vWf : Ag and large vWf multimer were 120.8 U/dL, 13.8% in MPD and 184.3 U/ dL, 20.7% in RT (P<0.05). Large vWf multimers were decreased in 11 MPDs and 2 RTs. Bleeding diathesis appeared only in 2 MPDs with decreased large vWf multimers. Platelet or leukocyte count was inversely correlated with large vWf multimers, but vWf antigen was correlated with large vWf multimer. CONCLUSION: The findings of normal vWf antigen level and decreased percentage of large vWf multimers are more frequent in MPD than in RT, and the measurement of these parameters is useful to differentiate MPD from RT. Bleeding complication in the patients with MPD with decreased large vWf multimers might be prevented by correction of decreased large vWf multimers.