A novel syndrome of radiation-associated acute myeloid leukemia involving AML1 gene translocations

Blood ◽  
2000 ◽  
Vol 95 (12) ◽  
pp. 4011-4013 ◽  
Author(s):  
Robert Hromas ◽  
Rinah Shopnick ◽  
Hani George Jumean ◽  
Charles Bowers ◽  
Marileila Varella-Garcia ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
World War Ii ◽  
Myeloid Leukemia ◽  
World War ◽  
Nuclear Explosions ◽  
Radiation Induced ◽  
Aml1 Gene ◽  
High Level ◽  
Acute Myeloid

Abstract AML1 is a transcriptional activator that is essential for normal hematopoietic development. It is the most frequent target for translocations in acute leukemia. We recently identified 3 patients in whom pancytopenia developed almost 50 years after high-level radiation exposure from nuclear explosions during or after World War II. In all 3 patients, acute myeloid leukemia (AML) eventually developed that had similar characteristics and clinical courses. Cytogenetics from the 3 patients revealed a t(1;21)(p36;q22), a t(18;21)(q21;q22), and a t(19;21)(q13.4;q22). By fluorescent in situ hybridization (FISH), all 3 translocations disrupted the AML1 gene. Two of theseAML1 translocations, the t(18;21) and the t(19;21), have not been reported previously. It is possible that the AML1 gene is a target for radiation-induced AML.

A novel syndrome of radiation-associated acute myeloid leukemia involving AML1 gene translocations

Blood ◽  
2000 ◽  
Vol 95 (12) ◽  
pp. 4011-4013 ◽  
Author(s):  
Robert Hromas ◽  
Rinah Shopnick ◽  
Hani George Jumean ◽  
Charles Bowers ◽  
Marileila Varella-Garcia ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
World War Ii ◽  
Myeloid Leukemia ◽  
World War ◽  
Nuclear Explosions ◽  
Radiation Induced ◽  
Aml1 Gene ◽  
High Level ◽  
Acute Myeloid

AML1 is a transcriptional activator that is essential for normal hematopoietic development. It is the most frequent target for translocations in acute leukemia. We recently identified 3 patients in whom pancytopenia developed almost 50 years after high-level radiation exposure from nuclear explosions during or after World War II. In all 3 patients, acute myeloid leukemia (AML) eventually developed that had similar characteristics and clinical courses. Cytogenetics from the 3 patients revealed a t(1;21)(p36;q22), a t(18;21)(q21;q22), and a t(19;21)(q13.4;q22). By fluorescent in situ hybridization (FISH), all 3 translocations disrupted the AML1 gene. Two of theseAML1 translocations, the t(18;21) and the t(19;21), have not been reported previously. It is possible that the AML1 gene is a target for radiation-induced AML.

scholarly journals De novo adult acute myeloid leukemia with two new mutations in juxtatransmembrane domain of the FLT3 gene: a case report

2021 ◽  
Vol 15 (1) ◽  
Author(s):  
Ismael F. Alarbeed ◽  
Abdulsamad Wafa ◽  
Faten Moassass ◽  
Bassel Al-Halabi ◽  
Walid Al-Achkar ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Chromosomal Abnormalities ◽  
Molecular Genetic ◽  
Type A ◽  
Chemotherapeutic Treatment ◽  
Acute Myeloid ◽  
New Mutations

Abstract Background Approximately 30% of adult acute myeloid leukemia (AML) acquire within fms-like tyrosine kinase 3 gene (FLT3) internal tandem duplications (FLT3/ITDs) in their juxtamembrane domain (JMD). FLT3/ITDs range in size from three to hundreds of nucleotides, and confer an adverse prognosis. Studies on a possible relationship between of FLT3/ITDs length and clinical outcomes in those AML patients were inconclusive, yet. Case presentation Here we report a 54-year-old Arab male diagnosed with AML who had two FLT3-ITD mutations in addition to NPM1 mutation. Cytogenetic approaches (banding cytogenetics) and fluorescence in situ hybridization (FISH) using specific probes to detect translocations t(8;21), t(15;17), t(16;16), t(12;21), and deletion del(13q)) were applied to exclude chromosomal abnormalities. Molecular genetic approaches (polymerase chain reaction (PCR) and the Sanger sequencing) identified a yet unreported combination of two new mutations in FLT3-ITDs. The first mutation induced a frameshift in JMD, and the second led to a homozygous substitution of c.1836T>A (p.F612L) also in JMD. Additionally a NPM1 type A mutation was detected. The first chemotherapeutic treatment was successful, but 1 month after the initial diagnosis, the patient experienced a relapse and unfortunately died. Conclusions To the best of our knowledge, a combination of two FLT3-ITD mutations in JMD together with an NPM1 type A mutation were not previously reported in adult AML. Further studies are necessary to prove or rule out whether the size of these FLT3-ITDs mutations and potential other double mutations in FLT3-ITD are correlated with the observed adverse outcome.

AML1 is expressed in skeletal muscle and is regulated by innervation

1994 ◽  
Vol 14 (12) ◽  
pp. 8051-8057
Author(s):  
X Zhu ◽  
J E Yeadon ◽  
S J Burden
Keyword(s):  
Skeletal Muscle ◽  
Acute Myeloid Leukemia ◽  
Electrical Activity ◽  
Myeloid Leukemia ◽  
Structure And Function ◽  
Denervated Muscle ◽  
Aml1 Gene ◽  
Low Levels ◽  
And Function ◽  
Acute Myeloid

Although most skeletal muscle genes are expressed at similar levels in electrically active, innervated muscle and in electrically inactive, denervated muscle, a small number of genes, including those encoding the acetylcholine receptor, N-CAM, and myogenin, are expressed at significantly higher levels in denervated than in innervated muscle. The mechanisms that mediate electrical activity-dependent gene regulation are not understood, but these mechanisms are likely to be responsible, at least in part, for the changes in muscle structure and function that accompany a decrease in myofiber electrical activity. To understand how muscle activity regulates muscle structure and function, we used a subtractive-hybridization and cloning strategy to identify and isolate genes that are expressed preferentially in innervated or denervated muscle. One of the genes which we found to be regulated by electrical activity is the recently discovered acute myeloid leukemia 1 (AML1) gene. Disruption and translocation of the human AML1 gene are responsible for a form of acute myeloid leukemia. AML1 is a DNA-binding protein, but its normal function is not known and its expression and regulation in skeletal muscle were not previously appreciated. Because of its potential role as a transcriptional mediator of electrical activity, we characterized expression of the AML1 gene in innervated, denervated, and developing skeletal muscle. We show that AML1 is expressed at low levels in innervated skeletal muscle and at 50- to 100-fold-higher levels in denervated muscle. Four AML1 transcripts are expressed in denervated muscle, and the abundance of each transcript increases after denervation. We transfected C2 muscle cells with an expression vector encoding AML1, tagged with an epitope from hemagglutinin, and we show that AML1 is a nuclear protein in muscle. AML1 dimerizes with core-binding factor beta (CBF beta), and we show that CGF beta is expressed at high levels in both innervated and denervated skeletal muscle. PEBP2 alpha, which is structurally related to AML1 and which also dimerizes with CBF beta, is expressed at low levels in skeletal muscle and is up-regulated only weakly by denervation. These results are consistent with the idea that AML1 may have a role in regulating gene expression in skeletal muscle.

Childhood Acute Myeloid Leukemia shows a high level of germline predisposition

Blood ◽  
2021 ◽  
Author(s):  
Saumya E Samaraweera ◽  
Paul Po-Shen Wang ◽  
Ka Leung Li ◽  
Debora A. Casolari ◽  
Jinghua Feng ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Childhood Acute Myeloid Leukemia ◽  
High Level ◽  
Acute Myeloid

scholarly journals DNA damage in acute myeloid leukemia patients of Northern Mexico

2017 ◽  
Author(s):  
Martha I. Dávila-Rodríguez ◽  
Elva I. Cortés-Gutiérrez ◽  
Roberto Hernández-Valdés ◽  
Karla Guzmán-Cortés ◽  
Rosa E. De León-Cantú ◽  
...  
Keyword(s):  
Dna Damage ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Fluorescent In Situ Hybridization ◽  
Control Group ◽  
Repair Pathway ◽  
Blood Leukocytes ◽  
Northern Mexico ◽  
Acute Myeloid

The purpose of this study was to evaluate DNA damage in the whole genome of peripheral blood leukocytes from patients with acute myeloid leukemia (AML) compared with a control group using DNA breakage detection-fluorescent in situ hybridization (DBD-FISH). Our results suggest that the DNA damage detected in patients with newly diagnosed AML was similar to that observed for the controls; this might be explained by the stimulation of a repair pathway by the pathogenesis itself. These findings indicate that inhibiting the repair pathway could be proposed to enhance the efficacy of chemotherapy.

scholarly journals Early Fluorescence in situ Hybridization Assessment during Acute Myeloid Leukemia Induction Chemotherapy

2018 ◽  
Vol 139 (3) ◽  
pp. 171-175
Author(s):  
Robert Schneidewend ◽  
Paul Hosking ◽  
Ruta Brazauskas ◽  
Jess Peterson ◽  
Carlie Beaudin ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
In Situ Hybridization ◽  
Fluorescence In Situ Hybridization ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
Acute Myeloid

Atypical Phenotype and Treatment Response Pattern in a Patient with FIP1L1-PDGFRα Mutation

2018 ◽  
Vol 140 (2) ◽  
pp. 67-70 ◽  
Author(s):  
Mihir Bikhchandani ◽  
Ryan Johnson ◽  
Bertrand Tuan ◽  
Ayalew Tefferi
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Myeloproliferative Neoplasm ◽  
Myeloproliferative Disorders ◽  
Second Line ◽  
Imatinib Resistance ◽  
Hypercellular Marrow ◽  
Atypical Phenotype ◽  
Acute Myeloid

Myeloproliferative disorders with eosinophilia may possess the FIP1L1-PDGFRα gene rearrangement. When this rearrangement is present, imatinib usually results in complete remission. In rare cases of imatinib resistance, there is poor evidence guiding second-line therapy. We present the case of a 71-year-old male who presented with abdominal discomfort, fevers, and leukocytosis with eosinophilia. The patient was diagnosed with a myeloproliferative neoplasm with eosinophilia and FIP1L1-PDGFRα rearrangement after a bone marrow evaluation revealed hypercellular marrow with eosinophilia and fluorescence in situ hybridization identified the FIP1L1-PDGFRα rearrangement. The patient was successfully treated with imatinib. Within months he relapsed and converted into acute myeloid leukemia. The patient was then treated with ponatinib which induced and maintained clinical and hematological remission for 2 months. That ponatinib briefly induced remission in our patient with acute myeloid leukemia arising from a myeloproliferative neoplasm with eosinophilia and FIP1L1-PDGFRα fusion may merit exploration of ponatinib as a potential second-line treatment option for this patient population. This is especially true given the lack of reliable therapies in instances of imatinib resistance.

scholarly journals The Curcumin Analogue, EF-24, Triggers p38 MAPK-Mediated Apoptotic Cell Death via Inducing PP2A-Modulated ERK Deactivation in Human Acute Myeloid Leukemia Cells

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2163
Author(s):  
Pei-Ching Hsiao ◽  
Jer-Hwa Chang ◽  
Wei-Jiunn Lee ◽  
Chia-Chi Ku ◽  
Meng-Ying Tsai ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Protein Kinase ◽  
Solid Tumors ◽  
Myeloid Leukemia ◽  
Apoptotic Cell ◽  
Mitogen Activated Protein Kinase ◽  
Therapeutic Benefits ◽  
Acute Myeloid Leukemia Cells ◽  
High Level ◽  
Acute Myeloid

Curcumin (CUR) has a range of therapeutic benefits against cancers, but its poor solubility and low bioavailability limit its clinical use. Demethoxycurcumin (DMC) and diphenyl difluoroketone (EF-24) are natural and synthetic curcumin analogues, respectively, with better solubilities and higher anti-carcinogenic activities in various solid tumors than CUR. However, the efficacy of these analogues against non-solid tumors, particularly in acute myeloid leukemia (AML), has not been fully investigated. Herein, we observed that both DMC and EF-24 significantly decrease the proportion of viable AML cells including HL-60, U937, and MV4-11, harboring different NRAS and Fms-like tyrosine kinase 3 (FLT3) statuses, and that EF-24 has a lower half maximal inhibitory concentration (IC50) than DMC. We found that EF-24 treatment induces several features of apoptosis, including an increase in the sub-G1 population, phosphatidylserine (PS) externalization, and significant activation of extrinsic proapoptotic signaling such as caspase-8 and -3 activation. Mechanistically, p38 mitogen-activated protein kinase (MAPK) activation is critical for EF-24-triggered apoptosis via activating protein phosphatase 2A (PP2A) to attenuate extracellular-regulated protein kinase (ERK) activities in HL-60 AML cells. In the clinic, patients with AML expressing high level of PP2A have the most favorable prognoses compared to various solid tumors. Taken together, our results indicate that EF-24 is a potential therapeutic agent for treating AML, especially for cancer types that lose the function of the PP2A tumor suppressor.

scholarly journals Prognostic Value of Metaphase-Fluorescence In Situ Hybridization in Follow-up of Patients With Acute Myeloid Leukemia in Remission

Blood ◽  
1997 ◽  
Vol 89 (9) ◽  
pp. 3330-3334 ◽  
Author(s):  
Wa'el El-Rifai ◽  
Tapani Ruutu ◽  
Erkki Elonen ◽  
Liisa Volin ◽  
Sakari Knuutila
Keyword(s):  
Acute Myeloid Leukemia ◽  
In Situ Hybridization ◽  
Fluorescence In Situ Hybridization ◽  
Myeloid Leukemia ◽  
Allogeneic Bone Marrow Transplantation ◽  
Leukemic Cells ◽  
Allogeneic Bone ◽  
Abnormal Cells ◽  
Acute Myeloid

Abstract The presence of residual leukemic cells was studied using metaphase-fluorescence in situ hybridization (FISH) in 22 patients with acute myeloid leukemia treated with chemotherapy only or chemotherapy followed by allogeneic bone marrow transplantation. The patients were followed up during their complete remission (CR) for 4 to 108 months (median, 21 months). A total of 88 BM samples was studied. In most of the samples more than 1,000 metaphase cells were analyzed. Residual leukemic cells were detected in 9 of 22 patients (41%). All patients who had an increasing and/or persisting level of abnormal cells in two or more subsequent samples or whose initial samples contained more than 1% of abnormal cells relapsed with one exception, in whom the later subsequent samples showed disappearance of abnormal cells. The time span before the first positive sample seems to be insignificant with regard to the outcome of relapse. Absence or single occurrence of abnormal cells followed by their disappearance was in agreement with CR in all the cases (16 patients). Our results indicate that metaphase-FISH is a reliable tool in the quantitation of residual leukemic cells and provides valuable prognostic information for patients with AML.

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