Internal tandem duplication of FLT3 in relapsed acute myeloid leukemia: a comparative analysis of bone marrow samples from 108 adult patients at diagnosis and relapse

Blood ◽  
2002 ◽  
Vol 100 (7) ◽  
pp. 2387-2392 ◽  
Author(s):  
Lee-Yung Shih ◽  
Chein-Fuang Huang ◽  
Jin-Hou Wu ◽  
Tung-Liang Lin ◽  
Po Dunn ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Residual Disease ◽  
Adult Patients ◽  
Single Mutation ◽  
Wild Type ◽  
First Relapse ◽  
Acute Myeloid

Analysis of internal tandem duplications of FLT3(FLT3/ITD) was performed on bone marrow samples obtained at diagnosis and relapse from 108 adult patients with de novo acute myeloid leukemia (AML) to determine the role of this mutation in leukemic relapse. Eighty-three patients had wild-type FLT3at both diagnosis and relapse, 16 had FLT3/ITD at both stages, whereas 8 had acquired the mutation and 1 had lost it at relapse. Using Genescan analysis, we found that FLT3/ITD levels at first relapse were significantly higher than those at diagnosis (mean ± SE, 40.5% ± 4.8% versus 17.9% ± 3.6%,P < .001). The increase in mutation levels at relapse as compared with diagnosis did not correlate with the difference in blast cell percentages at both stages (P = .777). A hemizygous deletion of wild-type FLT3 was found in 4 patients at relapse compared to none at diagnosis. Nine of the 11 patients carrying a single mutation at diagnosis relapsed with an identical mutation. All 6 patients with more than one FLT3/ITD mutation at diagnosis showed changes in mutation patterns and levels at first relapse; however, each patient retained at least one mutation in the relapse sample. The changes of mutation patterns had implications for the monitoring of minimal residual disease. Our results suggest thatFLT3/ITD may contribute as the initial transforming event in AML, and relapse can reflect the selection and outgrowth of a mutant clone or evolution of a new clone harboring this mutation.

scholarly journals Sox4 cooperates with PU.1 haploinsufficiency in murine myeloid leukemia

Blood ◽  
2011 ◽  
Vol 118 (17) ◽  
pp. 4674-4681 ◽  
Author(s):  
Georg Aue ◽  
Yang Du ◽  
Susan M. Cleveland ◽  
Stephen B. Smith ◽  
Utpal P. Davé ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Bone Marrow Cells ◽  
Regulatory Element ◽  
Mrna Levels ◽  
Wild Type ◽  
Myeloid Leukemias ◽  
Acute Myeloid

Abstract Cooperation of multiple mutations is thought to be required for cancer development. In previous studies, murine myeloid leukemias induced by transducing wild-type bone marrow progenitors with a SRY sex determining region Y-box 4 (Sox4)–expressing retrovirus frequently carried proviral insertions at Sfpi1, decreasing its mRNA levels, suggesting that reduced Sfpi1 expression cooperates with Sox4 in myeloid leukemia induction. In support of this hypothesis, we show here that mice receiving Sox4 virus-infected Sfpi1ko/+ bone marrow progenitors developed myeloid leukemia with increased penetrance and shortened latency. Interestingly, Sox4 expression further decreased Sfpi1 transcription. Ectopic SOX4 expression reduced endogenous PU.1 mRNA levels in HL60 promyelocytes, and decreased Sfpi1 mRNA levels were also observed in the spleens of leukemic and preleukemic mice receiving Sox4 virus-infected wild-type bone marrow cells. In addition, Sox4 protein bound to a critical upstream regulatory element of Sfpi1 in ChIP assays. Such cooperation probably occurs in de novo human acute myeloid leukemias, as an analysis of 285 acute myeloid leukemia patient samples found a significant negative correlation between SOX4 and PU.1 expression. Our results establish a novel cooperation between Sox4 and reduced Sfpi1 expression in myeloid leukemia development and suggest that SOX4 could be an important new therapeutic target in human acute myeloid leukemia.

scholarly journals Higher Expression of Suppressor of Cytokine Signaling1 (SOCS1) in the Bone Marrow Is an Unfavorable Prognostic Factor in Adult Patients with De Novo Acute Myeloid Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1034-1034
Author(s):  
Cheng-Hong Tsai ◽  
Hwei-Fang Tien ◽  
Hsin-An Hou ◽  
Wen-Chien Chou ◽  
Yan-Jun Lai ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Prognostic Factor ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Genetic Alterations ◽  
Adult Patients ◽  
Poor Prognostic Factor ◽  
Independent Poor Prognostic Factor ◽  
Acute Myeloid

Abstract Introduction Suppressor of cytokine signaling1 (SOCS1) protein, which encodes a member of the signal transducers and activators of transcription (STATs)-induced inhibitors, takes part in a negative regulation of cytokine signaling. The mechanism of SOCS1 in tumor carcinogenesis is complex and remains to be defined. Till now, there have been no studies concerning the prognostic implication of SOCS1 expression in acute myeloid leukemia (AML). Methods and Materials A total of 223 adult patients with newly diagnosed de novo AML who had enough cryopreserved cells for analysis at the National Taiwan University Hospital were enrolled consecutively. SOCS1 expression in bone marrow (BM) mononuclear cells was analyzed by quantitative real-time polymerase chain reaction. The results were correlated with FAB subtypes, clinical features, cytogenetics, other genetic alterations, and clinical outcome. Result The median value of SOCS1 expression was used as the cut-off value to divide patients into lower- and higher-expression groups. Higher SOCS1 expression was closely associated with older age (P=0.032) but inversely related to FAB M1 subtype and t(8;21)(q22;q22). There was no difference in other clinical parameters, including sex, hemoglobin level, white blood cell (WBC) counts, blast counts, and lactate dehydrogenase level between the two groups. Compared to patients with lower SOCS1 expression, those with higher expression had higher incidence of CD7 and CD34 expression on leukemic cells. To investigate the interactions of SOCS1 expression and other genetic alterations in the pathogenesis of AML, a complete mutational screening of 17 genes was performed. Higher SOCS1 expression was closely associated with NPM1 mutation and DNMT3A mutation (33% vs. 14.4%, P=0.002 and 20.9% vs. 10.8%, P=0.044, respectively), but negatively associated with CEBPA mutation (5.4% vs. 18.9%, P=0.002). Of the 154 AML patients receiving conventional intensive induction chemotherapy, 112 (72.7%) patients achieved complete remission (CR). The patients with higher SOCS1 expression had a lower probability of achieving CR than those with lower SOCS1 expression (62.9% vs. 81%, P=0.001). With a median follow-up time of 37 months (ranges, 0 to 160), patients with higher SOCS1 expression had poorer overall survival (OS) than those with lower SOCS1 expression (median 20 months vs. not reached, P=0.004). The same was also true among the patients with intermediate-risk cytogenetics and normal karyotype. In multivariate analysis, higher SOCS1 expression was an independent poor prognostic factor for OS in total cohort (relative risk, RR 1.947, 95% CI 1.081-3.508, P=0.026) irrespective of age, WBC, cytogenetics, NPM1/FLT3-ITD and CEBPA mutation. In the 77 cytogenetically-normal patients, higher SOCS1 expression was still an independent poor prognostic factor (RR 2.410, 95% CI 1.012-5.738, P=0.047). Interestingly, a scoring system incorporating SOCS1 expression and six other risk factors, including age, WBC, karyotype, FLT3/ITD, and mutations of NPM1 and CEBPA, into survival analysis was proved to be very useful to stratify AML patients into different risk groups (P =0.002). Conclusion AML patients with higher SOCS1 expression had distinct clinic-biologic features and poorer outcome. BM SOCS1 expression may serve as a new biomarker to risk stratify the patients. Disclosures No relevant conflicts of interest to declare.

AML1/RUNX1 mutations in 470 adult patients with de novo acute myeloid leukemia: prognostic implication and interaction with other gene alterations

Blood ◽  
2009 ◽  
Vol 114 (26) ◽  
pp. 5352-5361 ◽  
Author(s):  
Jih-Luh Tang ◽  
Hsin-An Hou ◽  
Chien-Yuan Chen ◽  
Chieh-Yu Liu ◽  
Wen-Chien Chou ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Remission Rate ◽  
Adult Patients ◽  
Poor Prognostic Factor ◽  
The Impact ◽  
Runx1 Mutation ◽  
Acute Myeloid

AbstractSomatic mutation of the AML1/RUNX1(RUNX1) gene is seen in acute myeloid leukemia (AML) M0 subtype and in AML transformed from myelodysplastic syndrome, but the impact of this gene mutation on survival in AML patients remains unclear. In this study, we sought to determine the clinical implications of RUNX1 mutations in 470 adult patients with de novo non-M3 AML. Sixty-three distinct RUNX1 mutations were identified in 62 persons (13.2%); 32 were in N-terminal and 31, C-terminal. The RUNX1 mutation was closely associated with male sex, older age, lower lactic dehydrogenase value, French-American-British M0/M1 subtypes, and expression of HLA-DR and CD34, but inversely correlated with CD33, CD15, CD19, and CD56 expression. Furthermore, the mutation was positively associated with MLL/PTD but negatively associated with CEBPA and NPM1 mutations. AML patients with RUNX1 mutations had a significantly lower complete remission rate and shorter disease-free and overall survival than those without the mutation. Multivariate analysis demonstrated that RUNX1 mutation was an independent poor prognostic factor for overall survival. Sequential analysis in 133 patients revealed that none acquired novel RUNX1 mutations during clinical courses. Our findings provide evidence that RUNX1 mutations are associated with distinct biologic and clinical characteristics and poor prognosis in patients with de novo AML.

Detection of the JAK2V617F Mutation in Myeloproliferative Disorders by Melting Curve Analysis Using the LightCycler System

2006 ◽  
Vol 130 (7) ◽  
pp. 997-1003
Author(s):  
Randall J. Olsen ◽  
Zhouwen Tang ◽  
Daniel H. Farkas ◽  
David W. Bernard ◽  
Youli Zu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Clinical Laboratory ◽  
Melting Curve ◽  
Myeloproliferative Disorder ◽  
Curve Analysis ◽  
Melting Curve Analysis ◽  
Wild Type ◽  
Acute Myeloid

Abstract Context.—A specific mutation, JAK2V617F, was recently recognized as having diagnostic value for myeloproliferative disorders. No practical assay is currently available for routine use in a clinical laboratory. Objective.—We report the development of a real-time polymerase chain reaction melting curve analysis assay that is appropriate for molecular diagnostics testing. Design.—Specific primers and fluorescence resonance energy transfer probes were designed, and patients with a previously diagnosed myeloproliferative disorder, de novo acute myeloid leukemia, or reactive condition were selected. The DNA was extracted from fresh and archived peripheral blood and bone marrow specimens, and real-time polymerase chain reaction melting curve analysis was performed on the LightCycler platform (Roche Applied Science, Indianapolis, Ind). Results.—The JAK2 region was successfully amplified, and wild-type amplicons were reproducibly discriminated from JAK2V617F amplicons. Titration studies using homozygous wild-type and mutant cell lines showed the relative areas under a melting curve were proportional to allele proportion, and the assay reliably detected one mutant in 20 total cells. JAK2V617F was identified in patients previously diagnosed with a myeloproliferative disorder or acute myeloid leukemia transformed from myeloproliferative disorder, whereas a wild-type genotype was identified in patients with reactive conditions or de novo acute myeloid leukemia. Conclusions.—These findings demonstrate the suitability of this assay for identifying JAK2V617F in a clinical laboratory setting. Furthermore, the semiquantitative detection of JAK2V617F in archived specimens provides a new tool for studying the prognostic significance of this mutation.

scholarly journals High-dose etoposide, cyclophosphamide, and total body irradiation with allogeneic bone marrow transplantation for patients with acute myeloid leukemia in untreated first relapse: a study by the North American Marrow Transplant Group

Blood ◽  
1995 ◽  
Vol 85 (5) ◽  
pp. 1391-1395 ◽  
Author(s):  
RA Brown ◽  
SN Wolff ◽  
JW Fay ◽  
L Pineiro ◽  
RH Jr Collins ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Bone Marrow Transplantation ◽  
Myeloid Leukemia ◽  
Allogeneic Bone Marrow Transplantation ◽  
High Dose ◽  
Allogeneic Bone ◽  
First Relapse ◽  
Total Body ◽  
Acute Myeloid

Relapse is a major cause of treatment failure following allogeneic bone marrow transplantation (BMT) for acute myeloid leukemia (AML). To reduce the risk of relapse following BMT for patients with hematologic malignancy, our group developed a novel preparative regimen which combines high-dose etoposide with cyclophosphamide and total body irradiation (VPCyTBI). We now report the outcome of therapy with VPCyTBI followed by allogeneic BMT for 40 patients with AML in untreated first relapse. With the exception of increased stomatitis, the toxicity of this regimen was similar to that reported by others for CyTBI. Forty-four months after transplant the actuarial probabilities of disease-free survival (DFS), persistent or recurrent leukemia, and transplant related mortality were .29, .44, and .47 respectively. DFS was improved (P < .01) and risk of persistent or recurrent leukemia reduced (P = .005) among patients with significant (grade > or = 2) acute GVHD. Patients with 30% or more blasts on pre-BMT bone marrow examination were not at increased risk for persistent or recurrent leukemia. We conclude that VPCyTBI with allogeneic BMT is effective therapy for AML in untreated first relapse and that a randomized trial comparing this regimen with CyTBI is warranted.

scholarly journals High NPM1 mutant allele burden at diagnosis correlates with minimal residual disease at first remission in de novo acute myeloid leukemia

2019 ◽  
Vol 94 (8) ◽  
pp. 921-928 ◽  
Author(s):  
Sanjay S. Patel ◽  
Geraldine S. Pinkus ◽  
Lauren L. Ritterhouse ◽  
Jeremy P. Segal ◽  
Paola Dal Cin ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Minimal Residual Disease ◽  
Myeloid Leukemia ◽  
Mutant Allele ◽  
De Novo ◽  
Residual Disease ◽  
Allele Burden ◽  
First Remission ◽  
Minimal Residual ◽  
Acute Myeloid

Unrelated cord blood transplantation for adult patients with de novo acute myeloid leukemia

Blood ◽  
2004 ◽  
Vol 103 (2) ◽  
pp. 489-491 ◽  
Author(s):  
Jun Ooi ◽  
Tohru Iseki ◽  
Satoshi Takahashi ◽  
Akira Tomonari ◽  
Kashiya Takasugi ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cord Blood ◽  
Median Time ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Cord Blood Transplantation ◽  
Adult Patients ◽  
Blood Transplantation ◽  
Unrelated Cord Blood ◽  
Acute Myeloid

Abstract We report the results of unrelated cord blood transplantation (CBT) for 18 adult patients with de novo acute myeloid leukemia (AML). The median age was 43 years, the median weight was 55.2 kg, and the median number of cryopreserved nucleated cells was 2.51 × 107/kg. Seventeen patients had myeloid reconstitution and the median time to more than 0.5 × 109/L absolute neutrophil count was 23 days. A self-sustained platelet count more than 50 × 109/L was achieved in 16 patients at a median time of 49 days. Acute graft-versus-host disease (GVHD) above grade II occurred in 11 of 17 evaluable patients and chronic GVHD occurred in 14 of 17 evaluable patients. Fourteen patients are alive and free of disease at between 185 and 1332 days after transplantation. The probability of disease-free survival at 2 years was 76.6%. These results suggest that adult AML patients without suitable related or unrelated bone marrow donors should be considered as candidates for CBT.

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