scholarly journals JAK2 mutation 1849G>T is rare in acute leukemias but can be found in CMML, Philadelphia chromosome–negative CML, and megakaryocytic leukemia

Blood ◽  
2005 ◽  
Vol 106 (10) ◽  
pp. 3370-3373 ◽  
Author(s):  
Jaroslav Jelinek ◽  
Yasuhiro Oki ◽  
Vazganush Gharibyan ◽  
Carlos Bueso-Ramos ◽  
Josef T. Prchal ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Myeloproliferative Disorders ◽  
Janus Kinase ◽  
Myelogenous Leukemia ◽  
Hematologic Neoplasms ◽  
Jak2 Mutation ◽  
Acute Leukemias ◽  
Myelomonocytic Leukemia

AbstractAn activating 1849G>T mutation of JAK2 (Janus kinase 2) tyrosine kinase was recently described in chronic myeloproliferative disorders (MPDs). Its role in other hematologic neoplasms is unclear. We developed a quantitative pyrosequencing assay and analyzed 374 samples of hematologic neoplasms. The mutation was frequent in polycythemia vera (PV) (86%) and myelofibrosis (95%) but less prevalent in acute myeloid leukemia (AML) with an antecedent PV or myelofibrosis (5 [36%] of 14 patients). JAK2 mutation was also detected in 3 (19%) of 16 patients with Philadelphia-chromosome (Ph)–negative chronic myelogenous leukemia (CML), 2 (18%) of 11 patients with megakaryocytic AML, 7 (13%) of 52 patients with chronic myelomonocytic leukemia, and 1 (1%) of 68 patients with myelodysplastic syndromes. No mutation was found in Ph+CML (99 patients), AML M0-M6 (28 patients), or acute lymphoblastic leukemia (20 patients). We conclude that the JAK2 1849G>T mutation is common in Ph– MPD but not critical for transformation to the acute phase of these diseases and that it is generally rare in aggressive leukemias.

Janus Kinase (JAK)-2 Does Not Play a Role in Bcr-Abl Signaling in Philadelphia Chromosome (Ph)-Positive (p190) Acute Lymphoblastic Leukemia (ALL) Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4241-4241
Author(s):  
Stefan H. Faderl ◽  
Quin Van ◽  
Patricia E. Koch ◽  
David M. Harris ◽  
Inbal Hallevi ◽  
...  
Keyword(s):  
Cell Lines ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Janus Kinase ◽  
Myelogenous Leukemia ◽  
Dependent Manner ◽  
Western Immunoblotting ◽  
Gm Csf ◽  
Dose Dependent

Abstract Novel immunochemotherapy regimens combined with imatinib mesylate (IA) have significantly improved treatment outcome of Ph+ ALL. Nevertheless, most adult patients with Ph+ ALL relapse and succumb to their disease. Recent reports suggested that Jak-2 is engaged in the signaling of Bcr-Abl in chronic myelogenous leukemia (CML) cells. Because Jak-2 inhibitory agents are currently investigated in clinical trials, we sought to explore the role of Jak-2 in the signaling of Bcr-Abl in Ph+ ALL assuming that inhibition of Jak-2 might be beneficial in the treatment of Ph+ ALL. To do this, we used our Ph+ (p190) ALL cell lines Z-119 and Z-181 (Estrov et al. J Cell Physiol166: 618, 1996). We chose these cells because in both lines Jak-2 can be activated. Both Z-119 and Z-181 cells express granulocyte-macrophage colony-stimulating factor (GM-CSF) receptors and GM-CSF activates Jak-2 and stimulates the proliferation of both cell lines. Using a clonogenic assay, we found that IA inhibited the proliferation of these cells at concentrations ranging from 50 to 500 nM. Because Bcr-Abl was found to activate the signal transducer and activator of transcription (STAT)-5 in CML cells, we used Western immunoblotting and found that IA inhibited the phosphorylation (p) of STAT5 in a dose-dependent manner in Ph+ ALL cells. To test whether JAk-2 plays a role in Bcr-Abl (p190) signaling we incubated Z-181 cells for 4 hours with or without 50, 100, 250, and 500 nM IA, extracted cellular protein and immunoprecipitated total STAT5 protein. Then, using Western immunoblotting we detected the Bcr-Abl p190 protein in all STAT5 immunoprecipitates and by using specific pSTAT5 antibodies, we demonstrated that IA induced a dose-dependent reduction in the levels of pSTAT5, but not of p190 protein, suggesting that the p190 Bcr-Abl kinase binds to and activates STAT5. Remarkably, neither Jak-2 nor pJak-2 was detected in either immunoprecipitate. To further delineate the role of Jak-2 in Bcr-Abl signaling we extracted protein from Z-181 cells and immunoprecipitated Jak-2. Neither Bcr-Abl nor STAT5 was detected in these immunoprecipitates, confirming that Jak-2 does not bind Bcr-Abl p190 protein and does not participate in the activation of STAT5. Taken together, our data suggest that Bcr-Abl (p190) binds and phosphorylates STAT5 whereas, Jak-2 is not engaged in Bcr-Abl (p190) signaling in Ph+ ALL cells.

Once-Daily Dasatinib for Treatment of Patients with Chronic Myeloid Leukemia

2009 ◽  
Vol 43 (5) ◽  
pp. 920-927 ◽  
Author(s):  
Timothy Tyler
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Chronic Myelogenous Leukemia ◽  
Myeloid Leukemia ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Myelogenous Leukemia ◽  
Once Daily ◽  
Number Of Patients ◽  
Significant Difference ◽  
American Society

Objective To discuss the new dasatinib dosing regimen for the treatment of chronic phase chronic myelogenous leukemia (CP CML) in patients who failed or were intolerant to imatinib therapy. Data Sources Literature published between July 2008 and December 2008 was accessed via MEDLINE, the Proceedings of the American Society of Hematology, and the Proceedings of the American Society of Clinical Oncology using the key words chronic myelogenous leukemia, chronic myeloid leukemia, dasatinib, imatinib, nilotinib, pharmacokinetics, and regimen. Study Selection And Data Extraction Meeting abstracts and reports of major Phase 1–3 studies published in English are included. Data Synthesis Imatinib is the standard first-line therapy for CML; however, some patients develop resistance or are intolerant to the drug. Dasatinib was approved for the treatment of imatinib-resistant/intolerant patients with CML or Philadelphia chromosome–positive acute lymphoblastic leukemia at the dosage of 70 mg twice daily. A Phase 3 dose-optimization study was performed to compare this regimen with others, including dasatinib 100 mg once daily, in patients with CP CML. Results of this study showed that there was no significant difference in efficacy between these 2 regimens. The safety profile was improved in the 100-mg once-daily dasatinib arm with significantly reduced frequencies of grade 3–4 thrombocytopenia and all-grade pleural effusions. The number of patients who had to discontinue, reduce, or interrupt their dosage was also less among patients taking dasatinib 100 mg once daily. Conclusions Dasatinib 100 mg once daily has a more favorable risk to benefit assessment compared with the previous 70 mg twice-daily regimen and is now the recommended schedule for patients with CP CML.

Mutant N-ras Induces Myeloproliferative Disorders and Apoptosis in Bone Marrow Repopulated Mice

Blood ◽  
1999 ◽  
Vol 93 (6) ◽  
pp. 2043-2056 ◽  
Author(s):  
K.L. MacKenzie ◽  
A. Dolnikov ◽  
M. Millington ◽  
Y. Shounan ◽  
G. Symonds
Keyword(s):  
Bone Marrow ◽  
Myeloid Leukemia ◽  
Philadelphia Chromosome ◽  
Myeloproliferative Disorders ◽  
Genetic Alterations ◽  
Myelogenous Leukemia ◽  
In Vivo Model ◽  
High Level

Mutations that activate the N-ras oncogene are among the most frequently detected genetic alterations in human acute myeloid leukemias (AMLs), Philadelphia chromosome-negative myeloproliferative disorders (MPDs), and myelodysplastic syndromes (MDSs). However, because N-ras has not been shown to induce these disorders in an in vivo model, the role of N-ras in the evolution of myeloid leukemia is unclear. To investigate the potential of N-ras to induce myeloid leukemia, lethally irradiated mice were reconstituted with bone marrow (BM) cells infected with a retroviral vector carrying activated N-ras. Approximately 60% of these mice developed hematopoietic disorders, including severe MPDs resembling human chronic myelogenous leukemia (CML) or AML with differentiation (French-American-British [FAB] classification M2). Other reconstituted mice succumbed to hematopoietic defects that were pathologically similar to human MDSs. The latter disorders appeared to be due to a myeloid impairment that was demonstrated by enumeration of day-12 colony-forming units-spleen (CFU-S) and by in vitro colony assays. A high level of apoptosis associated with thymic atrophy and peripheral blood (PB) lymphopenia was also evident in N-rasreconstituted mice. Our results are consistent with a model in which antiproliferative effects are a primary consequence of N-rasmutations and secondary transforming events are necessary for the development of myeloid leukemia. This is the first report of an in vivo model for N-ras induced MPD and leukemia.

BCR/ABL: The Clonal Bully

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4417-4417
Author(s):  
Abhinav Deol ◽  
Charles A. Schiffer
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Biopsy ◽  
Myeloid Leukemia ◽  
Myeloproliferative Disorders ◽  
Cytogenetic Response ◽  
Janus Kinase ◽  
Jak2 Mutation ◽  
Hematopoietic Stem ◽  
Hemoglobin A ◽  
Hematological Disorder

Abstract 4417 Chronic myeloid leukemia (CML) is characterized by the presence of t(9;22) leading to the BCR/ABL fusion gene while other myeloproliferative disorders such as polycytemia vera (PV) and primary myelofibrosis (PMF) may have a point mutation at V617 F codon of janus kinase 2 gene. Myelodysplastic syndrome (MDS) is thought to arise from an abnormality in the hematopoietic stem cell leading to impaired production of blood cells. In these diseases an abnormal clone proliferates and then suppresses normal hematopoiesis. We present 3 very unusual patients in whom CML was diagnosed a few years after the diagnosis of another clonal hematological disorder and in whom there was re-emergence of the original disorder after successful treatment of the CML. The first patient is an 88 yr old female who was diagnosed with PV in 1998 and treated with multiple phlebotomies, hydroxyurea and anagrelide. A bone marrow biopsy in 2002 showed the presence of the t(9;22) in 6 of 6 metaphases. She was treated with imatinib but failed to achieve a complete cytogenetic response and was switched to dasatinib which had to be stopped secondary to congestive heart failure. Nilotinib was then started but she developed QTc prolongation and failed to achieve a cytogenetic response. She was then managed with hydrea for many years and interestingly, manifested prominent cyclic leukocytosis. In 2010, analysis of blood showed a JAK2 mutation. She recently was begun on protocol treatment with ponatinib. Although moderate splenomegaly and leukocytosis persisted after 5 months of therapy, 0/26 metaphases demonstrated t (9;22) while gain/trisomy of 1q, an abnormality commonly seen in other myeloproliferative disorders and in particular, PV, was detected in 11/26 metaphases, The second patient is a 64 year old man who was initially diagnosed with PV during workup for elevated hematocrit in 2002. A JAK2 mutation was detected subsequently. Phlebotomy was discontinued in 2007 and he was maintained on hydroxyurea. In 2010, he was noted to have a WBC of 100,000/ul and underwent a bone marrow biopsy which showed the t(9;22). He was found to be in accelerated phase of CML and was initiated on dasatinib. At last follow up visit, the patient is in a cytogenetic remission for CML but was noted to have elevated hemoglobin; a repeat JAK2 is pending. The third patient is an 82 year old man who was diagnosed in 2005 with MDS with normal cytogenetics, when he was evaluated for macrocytic anemia. He was initially observed and subsequently treated with erythropoietin for decreasing hemoglobin. A bone marrow biopsy was repeated when his hemoglobin continued to decrease in 2009 and showed t(9;22) in 1/20 cells. He was started on imatinib and achieved a complete molecular response. About 3 months later he fractured his humerus and was found to have extramedullary acute myeloid leukemia which was positive by fluorescence in situ hybridization for BCR/ABL. His bone marrow at this time was negative for BCR/AB by RT-PCR but showed dysplatic changes. He was treated with radiotherapy to his arm and was switched to nilotinib. CML continues to be in a molecular remission, with low but stable blood counts. These 3 patients had an antecedent diagnosis of a clonal hematological disorder prior to developing CML. In 2 of the patients the CML became the dominant “bully” clone suppressing the manifestations of the PV clone. With targeted therapy directed at BCR/ABL, the CML clone was suppressed and the underlying disease again became apparent. In one patient, the presumed PV clone had evolved further with typical cytogenetic changes. It is unclear whether the CML developed from the original MPD/MDS clone or whether it represents an entirely independent disorder. In either event, the ability to successfully suppress the CML with specific therapy provides insights into the competitive interactions amongst abnormal clones and indeed, with normal hematopoiesis. Disclosures: No relevant conflicts of interest to declare.

Philadelphia chromosome and terminal transferase-positive acute leukemia: similarity of terminal phase of chronic myelogenous leukemia and de novo acute presentation.

1983 ◽  
Vol 1 (11) ◽  
pp. 669-676 ◽  
Author(s):  
K Jain ◽  
Z Arlin ◽  
R Mertelsmann ◽  
T Gee ◽  
S Kempin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Leukemia ◽  
Chronic Myelogenous Leukemia ◽  
Lymphoblastic Leukemia ◽  
Allogeneic Bone Marrow Transplantation ◽  
Philadelphia Chromosome ◽  
Myelogenous Leukemia ◽  
Allogeneic Bone ◽  
Leukocyte Antigen ◽  
Terminal Transferase

Twenty-eight patients with Philadelphia chromosome (Ph1)--positive and terminal transferase (TdT)--positive acute leukemia (AL) were treated with intensive chemotherapy used for adult acute lymphoblastic leukemia (L-10 and L-10M protocols). Fifteen patients had a documented chronic phase of Ph1-positive chronic myelogenous leukemia preceding the acute transformation (TdT + BLCML) while the remaining 13 patients did not (TdT + Ph1 + AL). An overall complete remission (CR) rate of 71% was obtained with a median survival of 13 months in the responders. Clinical presentation, laboratory data, cytogenetics, response to treatment, and survivals of the two groups of patients are compared. These results appear to be similar, suggesting a common or closely related origin. Since the overall survival of those receiving chemotherapy maintenance is poor, three patients underwent allogeneic bone marrow transplantation (BMT) from histocompatibility leukocyte antigen--matched siblings after they achieved CR. One of them is a long-term survivor (35 + months) with a Ph1-negative bone marrow. New techniques such as BMT should be considered in young patients with a histocompatibility leukocyte antigen--compatible sibling once a CR has been achieved.

scholarly journals Molecular analysis of interferon-induced suppression of Philadelphia chromosome in patients with chronic myeloid leukemia

Blood ◽  
1987 ◽  
Vol 69 (3) ◽  
pp. 961-963 ◽  
Author(s):  
G Yoffe ◽  
M Blick ◽  
H Kantarjian ◽  
G Spitzer ◽  
J Gutterman ◽  
...  
Keyword(s):  
Molecular Analysis ◽  
Myeloid Leukemia ◽  
Clinical Course ◽  
Philadelphia Chromosome ◽  
Myelogenous Leukemia ◽  
Human Interferon ◽  
Complete Suppression ◽  
Complete Disappearance ◽  
Course Of Disease ◽  
Normal Bone

Treatment with recombinant human interferon alpha-A (Roferon-A) is associated with stable suppression of the population of cells that display the Philadelphia (Ph1) chromosome in some patients with chronic myelogenous leukemia (CML) as defined by cytogenetic analysis. Southern blot analyses employing a 3′ breakpoint cluster region (bcr) probe (Pr- 1) were performed to confirm a complete suppression of the Ph1+ chromosome-positive clone of cells at the DNA level. The complete disappearance of rearranged restriction fragments of the bcr gene, which were a characteristic of the disease prior to Roferon-A therapy, was accompanied by the restoration of normal bone marrow and achievement of durable ongoing complete remission for 9 and 6 months, respectively, in two patients with Philadelphia-positive (Ph1+) CML. Molecular analysis is a valuable probe for monitoring the clinical course of disease in patients with Ph1+ CML.

Sign in / Sign up

Export Citation Format

Share Document