scholarly journals Classification, Diagnosis and Management of Myeloproliferative Disorders in the JAK2V617F Era

Hematology ◽  
2006 ◽  
Vol 2006 (1) ◽  
pp. 240-245 ◽  
Author(s):  
Ayalew Tefferi
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Mutation Screening ◽  
Myeloproliferative Disorders ◽  
Kinase Gene ◽  
Vein Thrombosis ◽  
Mutational Frequency ◽  
Abdominal Vein ◽  
Tyrosine Kinase Gene

Abstract JAK2V617F, a somatic gain-of-function mutation involving the JAK2 tyrosine kinase gene, occurs in nearly all patients with polycythemia vera (PV) but also in a variable proportion of patients with other myeloid disorders; mutational frequency is estimated at approximately 50% in both essential thrombocythemia (ET) and myelofibrosis (MF), up to 20% in certain subcategories of atypical myeloproliferative disorder (atypical MPD), less than 3% in de novo myelodysplastic syndrome (MDS) or acute myeloid leukemia, and 0% in chronic myeloid leukemia (CML). Accordingly, there is now molecular justification for grouping PV, ET, and MF together in a distinct MPD category (i.e., classic, BCR-ABL− MPD) that is separate from chronic myeloid leukemia (CML), MDS, and atypical MPD. To date, JAK2V617F has not been described in patients with reactive myeloproliferation, lymphoid disorders, or solid tumor. Therefore, the presence of JAK2V617F strongly suggests an underlying MPD and it is therefore reasonable to consider JAK2V617F-based laboratory tests for the evaluation of polycythemia, primary thrombocytosis, unexplained leukocytosis, bone marrow fibrosis, or abdominal vein thrombosis. Current information on disease-specific prognostic relevance of JAK2V617F is inconclusive and confounded by inter-study differences in the performance of mutation screening assays. Regardless, the discovery of JAK2V617F has reinforced the pathogenetic contribution of JAK-STAT signaling in MPD and identifies JAK2 as a valid drug target.

scholarly journals Clinical significance of dasatinib-induced pleural effusion in patients with de novo chronic myeloid leukemia

2018 ◽  
Vol 10 (3) ◽  
Author(s):  
Aya Nakaya ◽  
Shinya Fujita ◽  
Atsushi Satake ◽  
Takahisa Nakanishi ◽  
Yoshiko Azuma ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Clinical Features ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Late Onset ◽  
Molecular Response ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy ◽  
Treatment Agent

Dasatinib is currently approved for clinical use as a first-line treatment agent for newly diagnosed chronic myeloid leukemia (CML). However, only a few clinical trials have been performed to evaluate dasatinibinduced PE following first-line therapy. We investigated the incidence and clinical features of dasatinib-induced PE following first-line therapy in Japanese CML patients of real world clinical practice settings. Among 22 patients, the median age of PEpositive patients was higher than that of PEnegative patients. Major molecular response was achieved in 75% of PE-positive patients and 50% of PE-negative patients. Most patients developed PE more than 1 year after treatment. Appearance of PE is associated with better clinical response during dasatinib treatment, however it is developed at any time. Elderly and high-risk patients tend to develop PE. The clinical features of dasatinib-induced PE following first-line therapy might be late onset and might not immediately follow the increasing of large granular lymphocyte.

Cadherin-13, a Mediator of Calcium-Dependent Cell-Cell Adhesion, Is Silenced by Methylation in Chronic Myeloid Leukemia and Correlates With Pretreatment Risk Profile and Cytogenetic Response to Interferon Alfa

2003 ◽  
Vol 21 (8) ◽  
pp. 1472-1479 ◽  
Author(s):  
Jose Roman-Gomez ◽  
Juan A. Castillejo ◽  
Antonio Jimenez ◽  
Francisco Cervantes ◽  
Concepcion Boque ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Early Stage ◽  
Methylation Status ◽  
Chronic Phase ◽  
Progression Free Survival ◽  
Cytogenetic Response ◽  
Interferon Alfa ◽  
Advanced Phase

Purpose: Cadherin-13 (CDH13) is a newly characterized cadherin molecule responsible for selective cell recognition and adhesion, the expression of which is decreased by methylation in a variety of human cancers, indicating that the CDH13 gene functions as a tumor suppressor gene. Although defective progenitor-stromal adhesion is a well-recognized feature of chronic myeloid leukemia (CML), the role of CDH13 abnormalities has not been evaluated in this disease. Patients and Methods: We examined the methylation status of the CDH13 promoter in 179 chronic phase (CP)-CML patients and in 52 advanced-phase samples and correlated it with mRNA expression using methylation-specific polymerase chain reaction (PCR) and reverse transcriptase PCR. Results: Aberrant de novo methylation of the CDH13 promoter region was observed in 99 (55%) of 179 of CP-CML patients, and 90 of the patients failed to express CDH13 mRNA (P < .0001). Advanced-stage samples (n = 52) showed concordant methylation results with their corresponding CP tumors, indicating that CDH13 methylation was not acquired during the course of the disease. Nevertheless, absence of CDH13 expression was more frequently observed among Sokal high-risk patients (P = .01) and was also independently associated with a shorter median progression-free survival time (P = .03) and poor cytogenetic response to interferon alfa treatment (P = .0001). Conclusion: Our data indicate that the silencing of CDH13 expression by aberrant promoter methylation occurs at an early stage in CML pathogenesis and probably influences the clinical behavior of the disease.

scholarly journals Chromosome 3q21 abnormalities associated with hyperactive thrombopoiesis in acute blastic transformation of chronic myeloid leukemia

Blood ◽  
1986 ◽  
Vol 68 (3) ◽  
pp. 652-657 ◽  
Author(s):  
R Bernstein ◽  
A Bagg ◽  
M Pinto ◽  
D Lewis ◽  
B Mendelow
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Chromosome Translocation ◽  
Chromosome 9 ◽  
Chromosome 3 ◽  
Acute Megakaryoblastic Leukemia ◽  
Blastic Transformation ◽  
Megakaryoblastic Leukemia ◽  
Platelet Counts

Abstract Two patients with acute blastic transformation of chronic myeloid leukemia (CML) associated with strikingly elevated platelet counts showed abnormalities of chromosome 3q in addition to the standard Philadelphia (Ph1) chromosome translocation. The first patient had an inversion of chromosome 3 (q21q26) cytologically identical to an inversion 3 previously reported in de novo acute megakaryoblastic leukemia, and the second patient showed a translocation between chromosome 3q and the chromosome 9 homologue not involved in the Ph1 translocation, [t(3;9)(q21;q34)]. Previous studies had incriminated either 3q21 or 3q26 as the locus for a regulatory thrombopoietic gene, but the current study suggests that 3q21 is the relevant site.

Enumeration and Immunologic Characterization of Basophils in Normal Bone Marrow and Patients with Myeloproliferative Disorders.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4754-4754
Author(s):  
Hermine Agis ◽  
Maria T. Krauth ◽  
Leonhard Muellauer ◽  
Lawrence B. Schwartz ◽  
Hans P. Horny ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Histidine Decarboxylase ◽  
Chronic Phase ◽  
Myeloproliferative Disorders ◽  
Staining Procedure ◽  
Formalin Fixed Paraffin ◽  
Formalin Fixed Paraffin Embedded

Abstract Basophils are highly specialized granulocytes that express a unique profile of antigens and increase in myeloproliferative disorders. In chronic myeloid leukemia (CML), basophilia is an independent prognostic variable. So far, however, no reliable immunohistochemical approach for routine-detection and enumeration of bone marrow (bm) basophils has become available. To overcome this disadvantage, we have applied the anti-basophil antibody 2D7 on formalin-fixed, paraffin-embedded sections of normal bm and bm from patients (pts) with chronic myeloid leukemia (CML; chronic phase, n=21; accelerated phase, n=9), other myeloproliferative disorders (idiopathic myelofibrosis [IMF], n=3; polycythemia vera [PV], n=7; essential thrombocythemia [ET], n=7), and normal / reactive bm (n=32). As assessed by serial section-staining of bm specimens, the 2D7 antibody was found to be a basophil-specific immunohistochemical reagent. In serial bm sections, 2D7+ basophils co-expressed histidine decarboxylase, CD15, and CD43, but did not express B- or T-cell restricted antigens corresponding to the phenotype of normal blood basophils. Bm basophils were found to increase in number in pts with CML and other myeloproliferative disorders compared to normal bm (median 2D7+ cells/mm2 bm: normal bm: 7; CML: 46; IMF: 26; PV: 21; ET: 21, p&lt;.05). The highest numbers of bm basophils were recorded in pts with accelerated phase CML (111 2D7+ cells/mm2). Together, we have established a useful immunohistochemical staining procedure for basophil detection in normal bm and pts with myeloid neoplasms. This approach should enable the quantification of basophils in these pts and the monitoring of bm basophil counts during follow up examinations and anti-leukemic therapies.

Study of different mutations in chronic myeloid leukemia in India and their co-relation with drug resistance.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 7083-7083
Author(s):  
Priti Mitra ◽  
Swati Dasgupta ◽  
Chinmay Kumar Basu ◽  
Firoj Hossain Gharami ◽  
Subrata Mandal ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chromosomal Abnormalities ◽  
Mutation Screening ◽  
Resistance Mutation ◽  
Tyrosine Kinase Domain ◽  
Molecular Response ◽  
Imatinib Resistance ◽  
Imatinib Resistant ◽  
Resistant Mutation

7083 Background: Emergence of ABL point mutations is the most frequent cause for imatinib resistance in CML. Aim of our study is to investigate two potential resistance mechanisms i.e.,mutations of BCR-ABL tyrosine kinase domain (TKD) and Additional Chromosomal Abnormalities during TKI treatment in CML. Methods: Karyotyping and BCR-ABL TKD mutation screening are performed in 100 imatinib resistant CML patients who were on imatinib at the time of loss of hematologic response, cytogenetic or molecular response. Imatinib–Resistance Mutation Analysis (Qualitative) were detected by Nested RTPCR and Sanger’s Sequencing. In 100 cases, 34 received escalated imatinib, 34 nilotinib and another 32 dasatinib. Results: In 100 BCR-ABL positive imatinib, nilotinib and dasatinib resistant cases, 11 different BCR-ABL TKD mutations were detected. Analysis revealed no mutations-43 cases, M351T-12 cases, G250E-10 cases, F317L-8 cases, M244V-5 cases, E255K-4 cases, V379I-4 cases, F359V-3 cases, H396R-3 cases, Y253F-3 cases, E355G-3 cases, T315I-2 cases. 11 novel mutations (F317L, G250E, M244V, Y253F, E255K, M351T, F359V, H396R, V379I, E355G, T315I) conferring imatinib resistance, 10 nilotinib–resistant mutations (M244V, F359V, T315I, E355G, G250E) and 8 dasatinib-resistant mutations (H396R, F317L, H396R, T315I, M351T) were seen in our patient population. T315I was found more frequently in cases on dasatinib than on imatinib therapy. Conclusions: T315I which confers resistance to all TKIs was detected only in 2/100 patients who demonstrated loss of response in our population. As compared with other western studies, incidence of T315I mutation was very low in our study. In addition analysis of mutation patterns at baseline may help in stratifying patients for treatment. For cases with TKI resistance, mutation and ACA screening may play role in identifying patients with poorer prognosis. In our practice if nilotinib–resistant mutation was detected, dasatinib was preferred and for dasatinib-resistant mutation, nilotinib was preferred. We are planning for using bosutinib, panotinib and omacetaxine (SC route) in third line therapy in imatinib resistant different mutation positive chronic myeloid leukemia.

scholarly journals ELN 2013 response status criteria: Relevance for de novo imatinib chronic phase chronic myeloid leukemia patients?

2014 ◽  
Vol 90 (1) ◽  
pp. 37-41 ◽  
Author(s):  
Gabriel Etienne ◽  
Stéphanie Dulucq ◽  
Axelle Lascaux ◽  
Anna Schmitt ◽  
Audrey Bidet ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Chronic Phase ◽  
Response Status

scholarly journals Somatic Mutations in Oncogenes Are in Chronic Myeloid Leukemia Acquired De Novo via Deregulated Base-Excision Repair and Alternative Non-Homologous End Joining

2021 ◽  
Vol 11 ◽  
Author(s):  
Nikola Curik ◽  
Vaclava Polivkova ◽  
Pavel Burda ◽  
Jitka Koblihova ◽  
Adam Laznicka ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Base Excision Repair ◽  
Myeloid Leukemia ◽  
Somatic Mutations ◽  
De Novo ◽  
Excision Repair ◽  
Leukemic Cells ◽  
End Joining ◽  
Base Excision

Somatic mutations are a common molecular mechanism through which chronic myeloid leukemia (CML) cells acquire resistance to tyrosine kinase inhibitors (TKIs) therapy. While most of the mutations in the kinase domain of BCR-ABL1 can be successfully managed, the recurrent somatic mutations in other genes may be therapeutically challenging. Despite the major clinical relevance of mutation-associated resistance in CML, the mechanisms underlying mutation acquisition in TKI-treated leukemic cells are not well understood. This work demonstrated de novo acquisition of mutations on isolated single-cell sorted CML clones growing in the presence of imatinib. The acquisition of mutations was associated with the significantly increased expression of the LIG1 and PARP1 genes involved in the error-prone alternative nonhomologous end-joining pathway, leading to genomic instability, and increased expression of the UNG, FEN and POLD3 genes involved in the base-excision repair (long patch) pathway, allowing point mutagenesis. This work showed in vitro and in vivo that de novo acquisition of resistance-associated mutations in oncogenes is the prevalent method of somatic mutation development in CML under TKIs treatment.

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