AML1-ETO9a Correlated with C-KIT Overexpression/Mutation and Indicated Poor Disease Outcome in t(8;21) Acute Myeloid Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1822-1822
Author(s):  
Yang Liang ◽  
Bo Jiao ◽  
Chuan-Feng Wu ◽  
Shu-Min Xiong ◽  
Long-Jun Gu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Fusion Gene ◽  
Chromosome Translocation ◽  
Disease Outcome ◽  
Rt Pcr ◽  
Cell Counts ◽  
Short Overall Survival ◽  
White Blood Cell Counts ◽  
Acute Myeloid

Abstract AML1-ETO fusion gene is generated from chromosome translocation t(8;21) in acute myeloid leukemia (AML). It is recently reported that its spliced variant AML1-ETO9a induced leukemia rapidly in murine model. Here we detected AML1-ETO9a expression in 58 of 71 (81.7%) patients with t(8;21) AML by using qualitative RT-PCR. Quantitative RT-PCR revealed significantly higher C-KIT levels in the AML1-ETO9a positive group than in the negative group (P=0.0001). Among 29 cases harbored C-KIT mutations, 28 (96.6%) expressed AML1-ETO9a. Clinically, patients expressing AML1-ETO9a exhibited significantly elevated white blood cell counts and a short overall survival time (P=0.0455 and 0.0039, respectively). Morphologically, although there is no difference of leukemic blasts percentage between AML1-ETO9a positive and negative cases (P=0.1169), the latter possessed more aberrant myelocytes (P=0.0462). Taken together, AML1-ETO9a correlated with C-KIT overexpression/mutation and indicated poor disease outcome in t(8;21) AML.

APP Gene Is Correlated with C-KIT Mutations and Indicates Poor Disease Outcome in AML1-ETO-Positive Acute Myeloid Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 942-942
Author(s):  
Guopan Yu ◽  
Ling Jiang ◽  
Fan Yi Meng ◽  
Changxin Yin ◽  
Zhixiang Wang ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Fusion Gene ◽  
Prognostic Significance ◽  
Disease Outcome ◽  
Dynamic Monitoring ◽  
Qrt Pcr ◽  
Pcr Method ◽  
App Gene ◽  
Acute Myeloid

Abstract Amyloid precursor protein (APP) has been reported to be highly expressed in AML1-ETO-positive acute myeloid leukemia (AML1-ETO-positive AML), and we found it correlate with extramedullary infiltration regulated of by APP/ERK/MMP-2 signal pathway in our previous study. It is also known that C-KIT mutations highly expressed in AML1-ETO-positive AML and cooperates with full-length AML1-ETO to induce AML in mice. In this study we further described a close correlation of APP gene with C-KIT mutations, as well as APP related clinical and prognostic significance in 65 patients with AML1-ETO-positive AML. 65 cases of AML1-ETO-positive AML patients with median age of 30 years old, who were admitted to our hospital from February, 2006 to June, 2013 and made the diagnosis according to WHO2008 diagnosis standard, were enrolled into this study. APP expression in bone marrow cells before the first chemotherapy was assessed by quantitative reverse transcriptase (QRT)-PCR method. These cases were accordingly divided into APP-H group (n=33, with high level of APP by QRT-PCR) and APP-L group (n=32, with lower level of APP by QRT-PCR) according to median APP expression. Incidence of C-KIT mutations, clinical characteristics and prognosis including complete response (CR), overall survival (OS), and recurrence free survival (RFS) with median 35 (6-96) months followed-up was differentiated between the two groups. Furthermore, expression of APP and AML1/ETO fusion gene were simultaneously monitored at the time of 3, 6, 12 and 24 months or relapse after CR by QRT-PCR method. The incidence of C-KIT mutations was significantly increased in the APP-H group, as compared with the APP-L group (39.4% versus 12.5%) and it was positively correlative with APP expression (rp=0.435, P=0.004). Of the 17 patients harboring C-KIT mutations, 13 patients overexpressed APP gene (P=0.014) (Figure 1). Clinically, APP-H patients exhibited significantly elevated white blood cells count, increased extramedullary infiltration (P=0.039 and P=0.019, respectively). Moreover, APP overexpression was related to low rate of two-cycle CR, RFS and OS (P=0.020, P=0.001 and P=0.029, respectively) (Table 1). In addition, the change of APP expression was consistent with that of AML1-ETO fusion gene monitored by QRT-PCR method at different status of leukemia, though APP expressed differently in different patients with the same AML1-ETO expression. Taken together, these data suggest that APP gene is correlated with C-KIT mutations and indicates poor disease outcome and dynamic monitoring APP expression could be another choice of minimal residual disease monitoring in AML1-ETO-positive AML. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Molecular quantitation of minimal residual disease in acute myeloid leukemia with t(8;21) can identify patients in durable remission and predict clinical relapse

Blood ◽  
2000 ◽  
Vol 95 (3) ◽  
pp. 815-819 ◽  
Author(s):  
K. Tobal ◽  
J. Newton ◽  
M. Macheta ◽  
J. Chang ◽  
G. Morgenstern ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Fusion Gene ◽  
Clinical Relapse ◽  
Rt Pcr ◽  
Multicenter Studies ◽  
Degradation Rates ◽  
Durable Remission ◽  
Acute Myeloid

One of the most common translocations in acute myeloid leukemia (AML) is the t(8;21), which produces the fusion gene AML1-MTG8. We have developed a sensitive competitive reverse transcriptase-polymerase chain reaction (RT-PCR) assay forAML1-MTG8 transcripts, coupled with a competitive RT-PCR for the ABL transcript as a control to accurately estimate the level of amplifiable RNA. We have shown that AML1-MTG8 andABL transcripts have equal degradation rates. Thus, this method is useful for multicenter studies. We studied 25 patients with t(8;21) AML by means of serial analysis done on bone marrow (BM) and peripheral blood (PB) samples from 21 patients. Our analysis showed that, in general, a successful induction chemotherapy produces a reduction of 2 to 3 log in the level of AML1-MTG8, followed by a further 2 to 3 log after consolidation/intensification chemotherapy. Levels up to 1 × 103 and 1 × 102 molecules/μg of RNA in BM and PB, respectively, were compatible with durable remission. On the other hand, 5 patients with levels of 0.71 × 105to 2.27 × 105 molecules/μg of RNA in BM and 2.27 × 103 to 2.27 × 104 molecules/μg of RNA in PB had hematologic relapse within 3 to 6 months. Our data indicate that serial quantitation of AML1-MTG8 transcripts is useful in identifying patients at high risk of relapse and may offer an opportunity for clinical intervention to prevent hematologic relapse. This approach was applied successfully in a patient who had an allogeneic BM transplantation. We also suggest that PB may be used an alternative to BM for quantitating AML1-MTG8 transcripts.

scholarly journals First case report of a NUP98-PMX1 rearrangement in de novo acute myeloid leukemia and literature review

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Weijia Fu ◽  
Aijie Huang ◽  
Hui Cheng ◽  
Yanrong Luo ◽  
Lei Gao ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Fusion Gene ◽  
High Dose ◽  
Rt Pcr ◽  
Hematopoietic Stem ◽  
First Report ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Background The nucleoporin 98 (NUP98)-paired related homeobox 1 (PMX1) fusion gene, which results from t(1;11)(q23;p15), is rare in patients with acute myeloid leukemia (AML). Currently, only two cases of chronic myeloid leukemia in the accelerated phase or blast crisis and three cases of therapy-related AML have been reported. Here, we first report a patient with de novo AML carrying the NUP98-PMX1 fusion gene. Case presentation A 49-year-old man diagnosed with AML presented the karyotype 46,XY,t(1;11)(q23;p15)[20] in bone marrow (BM) cells. Fluorescence in situ hybridization analysis using dual-color break-apart probes showed the typical signal pattern. Reverse transcription-polymerase chain reaction (RT-PCR) analysis suggested the presence of the NUP98-PMX1 fusion transcript. The patient received idarubicin and cytarabine as induction chemotherapy. After 3 weeks, the BM aspirate showed complete remission, and the RT-PCR result for the NUP98-PMX1 fusion gene was negative. Subsequently, the patient received three cycles of high-dose Ara-c as consolidation chemotherapy, after which he underwent partially matched (human leukocyte antigen–DP locus mismatch) unrelated allogeneic hematopoietic stem cell transplantation (HSCT). The follow-up period ended on September 30, 2020 (6 months after HSCT), and the patient exhibited no recurrence or transplantation-related complications. Conclusion This is the first report of a patient with de novo AML carrying the NUP98-PMX1 fusion gene. The reported case may contribute to a more comprehensive profile of the NUP98-PMX1 rearrangement, but mechanistic studies are warranted to fully understand the role of this fusion gene in leukemia pathogenesis.

FIP1L1-PDGFRA Positive Secondary Acute Myeloid Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2362-2362
Author(s):  
Georgia Metzgeroth ◽  
Helena Popp ◽  
Christoph Walz ◽  
Martin C. Müller ◽  
Jürgen Mix ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Fusion Gene ◽  
Hypereosinophilic Syndrome ◽  
Chronic Phase ◽  
Response To Treatment ◽  
Clinical Feature ◽  
Rt Pcr ◽  
Secondary Aml ◽  
Acute Myeloid

Abstract The FIP1L1-PDGFRA positive myeloproliferative syndrome (MPS) represents a distinct clinicobiological entity with constitutively enhanced tyrosine kinase activity of the fusion protein and excellent response to treatment with imatinib. Most patients are initially diagnosed as idiopathic hypereosinophilic syndrome or chronic eosinophilic leukemia (CEL). A prominent clinical feature besides eosinophilia is the male predominance. However, the natural clinical course remains to be elucidated. Here we report on five male FIP1L1-PDGFRA positive patients (median age 58, range 46–64 years) with various subtypes of acute myeloid leukemia (AML) according to the FAB classification (M0, n=2; M2, n=1; M4eo, n=1; acute eosinophilic leukemia, n=1). All patients had a history of pronounced eosinophilia for a median interval of 6 mo (range 2–186) indicating the presence of a CML-like chronic phase disease evolving to blast crisis or secondary AML. One patient relapsed six years after conventional chemotherapy of a secondary FIP1L1-PDGFRA positive eosinophilia-associated AML M0 with typical features of CEL. Three patients had additional cytogenetic aberrations at diagnosis of AML similar to those frequently observed during clonal evolution of CML (trisomy 8, n=2; trisomy 9, n=1). All five patients received imatinib (100–300 mg/day) for a median time of 12 mo (range 1–23); three patients as monotherapy, one patient after one course and another patient after two courses of intensive chemotherapy. Three AML patients have been treated for more than 3 mo (12+, 18+, and 23+ mo) and are currently free of relapse. All three patients achieved a rapid complete hematological remission, defined as a complete clearance of blasts, normalization of peripheral blood and bone marrow eosinophil count, and a complete molecular remission 4, 5, and 14 mo, respectively, after start of treatment as determined by nested RT-PCR for the FIP1L1-PDGFRA transcript. In all cases treatment with imatinib was well tolerated. We conclude that the occurrence of the FIP1L1-PDGFRA fusion gene seems to be associated with a chronic phase disease which may progress to secondary AML. Therefore, all patients presenting with an eosinophilia-associated AML and normal karyotype should be screened for the cytogenetically invisible FIP1L1-PDGFRA fusion gene by RT-PCR and/or fluorescence in situ hybridization, in addition to the commoner CBFB-MYH11 fusion. Patients with a FIP1L1-PDGFRA positive MPS are excellent candidates for treatment with imatinib even if they present with secondary AML.

scholarly journals A rare case of acute myeloid leukemia with ARHGEF12 (LARG, 11q23.3) and MAPRE1 (EB1, 20q11.21) fusion gene in an elderly patient

2020 ◽  
Vol 28 (1) ◽  
pp. 99-106
Author(s):  
Ioan Macarie ◽  
Florin Tripon ◽  
Bogdana Dorcioman ◽  
Melania Macarie
Keyword(s):  
Elderly Patient ◽  
Acute Myeloid Leukemia ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Blood Smear ◽  
Group Performance ◽  
Fusion Gene ◽  
Peripheral Blood Smear ◽  
Rt Pcr ◽  
Acute Myeloid

AbstractIntroduction. We report one elderly patient diagnosed with a rare subtype of acute myeloid leukemia (AML) and also with a very rare fusion gene involving ARHGEF12 (LARG, 11q23.3) and MAPRE1 (EB1, 20q11.21) genes.Material and methods. Clinical examination and routine analysis were performed including peripheral blood smear, immunophenotyping of the peripheral blood by flow cytometry and several molecular analyses.Results. Peripheral blood smear showed 80% blasts with round and some with convoluted nuclei, with basophilic cytoplasm, identified as monoblast and the majority of cells as promonocytes. Peripheral blood immunophenotyping was consistent with monocytic differentiation. Molecular analysis was negative for FLT3 ITD, FLT3 D835, NPM1, and DNMT3A R882 mutations. Multiplex ligation-dependent probe amplification revealed no copy number aberration. Ligation-dependent reverse transcription polymerase chain reaction (LD-RT-PCR) analysis identified the presence of one gene fusion between ARHGEF12 (LARG, 11q23.3) and MAPRE1 (EB1, 20q11.21) genes. The patient had no significant comorbidities, the renal function was normal and Eastern Cooperative Oncology Group performance status was 2 at diagnosis and 1 after treatment. She was treated with decitabine. She became transfusion independent and a reduction of the number of blasts was obtained.Conclusions. The outcome of our AML patient was favorable but other patients with fusion genes involving ARHGEF12 (LARG, 11q23.3) and MAPRE1 (EB1, 20q11.21) should be reported, contributing to a better characterization of the disease, to monitor the minimal residual disease and in the end to more targeted treatment options. LD-RT-PCR represent a valuable multiplex technique for fusion gene analysis.

scholarly journals Impact of PTPN11 mutations on clinical outcome analyzed in 1529 patients with acute myeloid leukemia

2021 ◽  
Vol 5 (17) ◽  
pp. 3279-3289
Author(s):  
Sebastian Stasik ◽  
Jan-Niklas Eckardt ◽  
Michael Kramer ◽  
Christoph Röllig ◽  
Alwin Krämer ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Multivariable Analysis ◽  
Ras Signaling ◽  
Prognostic Impact ◽  
Poor Overall Survival ◽  
Cell Counts ◽  
Important Regulator ◽  
White Blood Cell Counts ◽  
Acute Myeloid

Abstract The tyrosine-protein phosphatase nonreceptor type 11 (PTPN11) is an important regulator of RAS signaling and frequently affected by mutations in patients with acute myeloid leukemia (AML). Despite the relevance for leukemogenesis and as a potential therapeutic target, the prognostic role is controversial. To investigate the prognostic impact of PTPN11 mutations, we analyzed 1529 adult AML patients using next-generation sequencing. PTPN11 mutations were detected in 106 of 1529 (6.93%) patients (median VAF: 24%) in dominant (36%) and subclonal (64%) configuration. Patients with PTPN11 mutations were associated with concomitant mutations in NPM1 (63%), DNMT3A (37%), and NRAS (21%) and had a higher rate of European LeukemiaNet (ELN) favorable cytogenetics (57.8% vs 39.1%; P < .001) and higher white blood cell counts (P = .007) compared with PTPN11 wild-type patients. In a multivariable analysis, PTPN11 mutations were independently associated with poor overall survival (hazard ratio [HR]: 1.75; P < .001), relapse-free survival (HR: 1.52; P = .013), and a lower rate of complete remission (odds ratio: 0.46; P = .008). Importantly, the deleterious effect of PTPN11 mutations was confined predominantly to the ELN favorable-risk group and patients with subclonal PTPN11 mutations (HR: 2.28; P < .001) but not found with dominant PTPN11 mutations (HR: 1.07; P = .775), presumably because of significant differences within the rate and spectrum of associated comutations. In conclusion, our data suggest an overall poor prognostic impact of PTPN11 mutations in AML, which is significantly modified by the underlying cytogenetics and the clonal context in which they occur.

scholarly journals Combined use of interferon alpha-1b, interleukin-2, and thalidomide to reverse the AML1-ETO fusion gene in acute myeloid leukemia

2021 ◽  
Author(s):  
Ruihua Mi ◽  
Lin Chen ◽  
Haiping Yang ◽  
Yan Zhang ◽  
Jia Liu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Interferon Alpha ◽  
Myeloid Leukemia ◽  
Clinical Medicine ◽  
Fusion Gene ◽  
Interleukin 2 ◽  
Effective Rate ◽  
Dose Administration ◽  
Combined Use ◽  
Acute Myeloid

AbstractThis study aims to explore the effect of the ITI (interferon alpha-1b, thalidomide, and interleukin-2) regimen on the AML1-ETO fusion gene in patients with t(8;21) acute myeloid leukemia (AML) who were in hematologic remission but positive for the AML1-ETO fusion gene. From September 2014 to November 2020; 20 patients with AML (15 from The Affiliated Cancer Hospital of Zhengzhou University, 4 from The First Affiliated Hospital; and College of Clinical Medicine of Henan University of Science and Technology, and 1 from Anyang District Hospital) with hematological remission but AML1-ETO fusion gene positivity were treated with different doses of the ITI regimen to monitor changes in AML1-ETO fusion gene levels. Twenty patients were treated with a routine dose of the ITI regimen, including 13 males and 7 females. The median patient age was 38 (14–70 years). The fusion gene was negative in 10 patients after 1 (0.5 ~ 8.6) month, significantly decreased in 4 patients after 2.8 (1 ~ 6) months, increased in 4 patients, and unchanged in 2 patients. The 4 patients with elevated levels of the fusion gene were treated with an increased dose of the ITI regimen, and all four patients became negative, for a total effective rate of 90%. The ITI regimen reduces AML1-ETO fusion gene levels in patients with AML who are in hematologic remission but are fusion gene–positive. Improvement was observed in patients’ response to a higher dose administration, and patients tolerated the treatment well.

scholarly journals The specific distribution pattern of IKZF1 mutation in acute myeloid leukemia

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Xiang Zhang ◽  
Xuewu Zhang ◽  
Xia Li ◽  
Yunfei Lv ◽  
Yanan Zhu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Genetic Alteration ◽  
Missense Mutations ◽  
Nonsense Mutations ◽  
Specific Distribution ◽  
Aggressive Clinical Course ◽  
Acute Myeloid

Abstract IKZF1 belongs to the IKAROS family of transcription factors, and its deletion/mutation frequently affects acute lymphoblastic leukemia. In acute myeloid leukemia, IKZF1 deletion has been demonstrated recurrent, but whether IKZF1 mutation also exists in AML remained largely unknown. Herein, we analyzed the IKZF1 mutation in AML. In our cohort, the frequency of IKZF1 mutation was 2.6% (5/193), and 5 frameshift/nonsense mutations as well as 2 missense mutations were identified in total. Molecularly, IKZF1 mutation was absent in fusion gene-positive AML, but it was demonstrated as the significant concomitant genetic alteration with SF3B1 or bi-alleleCEBPA mutation in AML. Clinically, two IKZF1, PTPN11 and SF3B1-mutated AML patients exhibited one aggressive clinical course and showed primary resistant to chemotherapy. Furthermore, we confirmed the recurrent IKZF1 mutation in AML with cBioPortal tool from OHSU, TCGA and TARGET studies. Interestingly, OHSU study also showed that SF3B1 mutation was the significant concomitant genetic alteration with IKZF1 mutation, indicating their strong synergy in leukemogenesis. In conclusion, IKZF1 mutation recurrently affected AML.

scholarly journals BAALC and ERG Expression in Egyptian Patients with Acute Myeloid Leukemia, Relation to Survival and Response to Treatment

2016 ◽  
Vol 4 (2) ◽  
pp. 264-270 ◽  
Author(s):  
Aml Soliman ◽  
Asmaa Abdel Aal ◽  
Reham Afify ◽  
Noha Ibrahim
Keyword(s):  
Polymerase Chain Reaction ◽  
Acute Myeloid Leukemia ◽  
Reverse Transcription ◽  
Myeloid Leukemia ◽  
Rt Pcr ◽  
Chain Reaction ◽  
Pcr Assay ◽  
Polymerase Chain ◽  
Age And Sex ◽  
Acute Myeloid

AIM: Aim was to detect Brain and Acute Leukemia, Cytoplasmic (BAALC) and ETS-related gene (ERG) expression in patients with acute myeloid leukemia (AML) as well as to study their biologic and prognostic impact on the disease outcome and survival.PATIENTS AND METHODS: The current study was carried out on 44 patients with denovo acute myeloid leukemia, as well as 44 age and sex matched controls. The quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) assay was performed for estimation of BAALC and ERG expression.RESULTS: The current study was carried out on 44 patients with denovo acute myeloid leukemia, as well as 44 age and sex matched controls. The quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) assay was performed for estimation of BAALC and ERG expression. BAALC was expressed in 36 (81.82%) of AML cases versus 10 (22.72%) of the control group which was highly statistically significant (P < 0.001). While ERG was positive in 39(88.64%) of cases and 8(18.18 %) of controls and that was also highly statistically significant (P < 0.001).CONCLUSION: Further researches still needed to clarify the role of BAALC and ERG in the pathogenesis of leukemia and their importance as targets for treatment of AML.

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