scholarly journals The Role of Forkhead Box Proteins in Acute Myeloid Leukemia

Cancers ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 865 ◽  
Author(s):  
Carmelo Gurnari ◽  
Giulia Falconi ◽  
Eleonora De Bellis ◽  
Maria Teresa Voso ◽  
Emiliano Fabiani
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Drug Sensitivity ◽  
Gene Mutations ◽  
World Health ◽  
Hematological Neoplasms ◽  
Forkhead Box ◽  
Health Organization ◽  
Acute Myeloid

Forkhead box (FOX) proteins are a group of transcriptional factors implicated in different cellular functions such as differentiation, proliferation and senescence. A growing number of studies have focused on the relationship between FOX proteins and cancers, particularly hematological neoplasms such as acute myeloid leukemia (AML). FOX proteins are widely involved in AML biology, including leukemogenesis, relapse and drug sensitivity. Here we explore the role of FOX transcription factors in the major AML entities, according to “The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia”, and in the context of the most recurrent gene mutations identified in this heterogeneous disease. Moreover, we report the new evidences about the role of FOX proteins in drug sensitivity, mechanisms of chemoresistance, and possible targeting for personalized therapies.

Role of FLT3 gene mutations in acute myeloid leukemia: effect on course of disease and results of therapy

2019 ◽  
Vol XIV (1) ◽  
Author(s):  
A.M. Radzhabova ◽  
S.V. Voloshin ◽  
I.S. Martynkevich ◽  
A.A. Kuzyaeva ◽  
V.A. Shuvaev ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Gene Mutations ◽  
Course Of Disease ◽  
Acute Myeloid

The Value of CD64 Expression in Distinguishing Acute Myeloid Leukemia With Monocytic Differentiation From Other Subtypes of Acute Myeloid Leukemia: A Flow Cytometric Analysis of 64 Cases

2007 ◽  
Vol 131 (5) ◽  
pp. 748-754
Author(s):  
Cherie H. Dunphy ◽  
Wohzan Tang
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Flow Cytometric Analysis ◽  
World Health ◽  
Monocytic Differentiation ◽  
Flow Cytometric Immunophenotyping ◽  
Cd64 Expression ◽  
Flow Cytometric ◽  
Health Organization ◽  
Acute Myeloid

Abstract Context.—Flow cytometric immunophenotyping is a useful ancillary tool in the diagnosis and subclassification of acute myeloid leukemias (AMLs). A recent study concluded that CD64 is sensitive and specific for distinguishing AMLs with a monocytic component (ie, AML M4 and AML M5) from other AML subtypes. However, in that study, the intensity of CD64 was not well defined and the number of non-M4/non-M5 AMLs was small. Objective.—To evaluate the usefulness of CD64 by flow cytometric immunophenotyping in distinguishing AMLs with monocytic differentiation from other AML subtypes. Design.—Sixty-four AMLs subclassified based on the French-American-British and World Health Organization classifications on pretreatment bone marrows were retrieved from our files (7 M0s, 11 M1s, 17 M2s, 7 M3s, 9 M4s, 7 M5s, 4 M6s, and 2 M7s). A standard panel of markers, including CD2, CD3, CD5, CD7, CD10, CD11b, CD13, CD14, CD15, CD19, CD20, CD33, CD34, CD45, CD56, CD64, CD117, and HLA-DR, were analyzed by flow cytometric immunophenotyping in all AMLs (52 bone marrow samples; 12 peripheral blood samples). Results.—CD64 was expressed in AML subtypes M0 to M5 in varying intensities: heterogeneously expressed in 1 of 7 M0s; dimly expressed in 3 of 11 M1s; dimly and moderately expressed in 6 and 2 of 17 M2s, respectively; dimly and moderately expressed in 5 and 1 of 7 M3s, respectively; dimly expressed in 4 of 9 M4s; and heterogeneously, moderately, and strongly expressed in 1, 3, and 3 of 7 M5s, respectively. Conclusions.—Strong CD64 expression distinguishes AML M5; however, heterogeneous, dim, or moderate expression in itself does not distinguish M0 through M4 subtypes from M5 with dim to moderate CD64 expression. However, any CD64 expression associated with strong CD15 expression distinguishes AML M4 or M5, from other AML subtypes.

Clinico-pathologic characteristics and outcomes of the World Health Organization (WHO) provisional entity de novo acute myeloid leukemia with mutated RUNX1

2020 ◽  
Vol 33 (9) ◽  
pp. 1678-1689
Author(s):  
Andrés E. Quesada ◽  
Guillermo Montalban-Bravo ◽  
Rajyalakshmi Luthra ◽  
Keyur P. Patel ◽  
Koji Sasaki ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
World Health Organization ◽  
Myeloid Leukemia ◽  
De Novo ◽  
World Health ◽  
The World ◽  
Health Organization ◽  
Acute Myeloid

Role of Gene Mutations in Adult Acute Myeloid Leukemia Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3373-3373
Author(s):  
Sheng-Chieh Chou ◽  
Jih-Luh Tang ◽  
Liang-In Lin ◽  
Hsin-An Hou ◽  
Chien-Yuan Chen ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myeloid Leukemia ◽  
Gene Mutations ◽  
Genetic Alterations ◽  
Prognostic Impact ◽  
Hematopoietic Stem ◽  
Wbc Count ◽  
Acute Myeloid

Abstract Abstract 3373 Poster Board III-261 Purpose Several gene mutations had been found to have clinical implications in patients with acute myeloid leukemia (AML), especially in those with normal karyotype. However, the role of such gene mutations for AML patients receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT) was unclear and inconclusive. We retrospectively evaluated the prognostic impact of 8 gene mutations in adult AML patients undergoing allo-HSCT. Materials & Methods From 1995 to 2007, a total of 463 consecutive adult patients with de novo non-M3 AML had comprehensive gene mutation analyses at the National Taiwan University Hospital. Three hundred and twenty five patients who received conventional induction chemotherapy were enrolled in this study. Those who received only low dose chemotherapy or palliative treatment were excluded. The genetic alterations analyzed included NPM1, FLT3/ITD, FLT3/TKD, CEBPA, AML1/RUNX1, RAS, MLL/PTD, and WT1. The clinical implication of these genetic alterations in the patients receiving allo-HSCT was analyzed, and the result was compared with that in patients without allo-HSCT. Results The clinical characteristics in the patients receiving allo-HSCT (n=100) and those without (n=225) were similar with the exception of age, being younger in the former group (35.4 years vs. 49.5 years p<0.001). In univariate analysis, older age (Age > 45 years), higher initial WBC count (WBC>50K/μL), elevated LDH level, unfavorable karyotype, FLT3/ITD, mutations of AML1/RUNX1 were significantly associated with poorer overall survival (OS) in patients not receiving allo-HSCT; While NPM1mut/FLT3ITDneg and CEBPA mutations served as significantly good prognostic indicators. In multivariate analysis, age, WBC count, karyotype, FLT3/ITD, AML1/RUNX1, CEBPA and NPM1mut/FLT3ITDneg remained to be independent prognostic factors in non-allo-HSCT patients. However, in patients receiving allo-HSCT, only unfavorable karyotype and disease status (refractory or remission) at the time of transplantation were associated with poorer OS both in univariate and multivariate analyses. The similar prognostic impact of FLT3/ITD, CEBPA, AML1/RUNX1 and NPM1 on OS was not seen in patients receiving allo-HSCT. Furthermore, in contrast to its poor prognostic impact in non-allo-HSCT patients, mutation of AML1/RUNX1 was a significant good prognostic factor for relapse free survival (p=0.046), although not for OS, in allo-HSCT group. Conclusion FLT3/ITD, mutations of AML1/RUNX1, CEBPA and NPM1 have great prognostic implication for OS in AML patients not receiving allo-HSCT. However, their impact on OS is ameliorated in patients receiving allo-HSCT. The results need to be confirmed by further studies on more patients. Disclosures: No relevant conflicts of interest to declare.

Morphologic Dysplasia in De Novo Acute Myeloid Leukemia (AML) Is Related to Unfavorable Cytogenetics but Has No Independent Prognostic Relevance Under the Conditions of Intensive Induction Therapy: Results of a Multiparameter Analysis From the German AML Cooperative Group Studies

2003 ◽  
Vol 21 (2) ◽  
pp. 256-265 ◽  
Author(s):  
Torsten Haferlach ◽  
Claudia Schoch ◽  
Helmut Löffler ◽  
Winfried Gassmann ◽  
Wolfgang Kern ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Who Classification ◽  
De Novo ◽  
World Health ◽  
Prognostic Impact ◽  
Cooperative Group ◽  
Prognostic Relevance ◽  
Health Organization ◽  
Acute Myeloid

Purpose: On the basis of cytomorphology according to the French-American-British (FAB) classification, we evaluated the prognostic impact of dysplastic features and other parameters in de novo acute myeloid leukemia (AML). We also assessed the clinical significance of the recently introduced World Health Organization (WHO) classification for AML, which proposed dysplasia as a new parameter for classification. Patients and Methods: We analyzed prospectively 614 patients with de novo AML, all of whom were diagnosed by central morphologic analysis and treated within the German AML Cooperative Group (AMLCG)-92 or the AMLCG-acute promyalocytic leukemia study. Results: Patients with AML M3, M3v, or M4eo demonstrated a better outcome compared with all other FAB subtypes (P < .001); no prognostic difference was observed among other FAB subtypes. The presence or absence of dysplasia failed to demonstrate prognostic relevance. Other prognostic markers, such as age, cytogenetics, presence of Auer rods, and lactate dehydrogenase (LDH) level at diagnosis, all showed significant impact on overall and event-free survival in univariate analyses (P < .001 for all parameters tested). However, in a multivariate analysis, only cytogenetics (unfavorable or favorable), age, and high LDH maintained their prognostic impact. Dysplasia was not found to be an independent prognostic parameter, but the detection of trilineage dysplasia correlated with unfavorable cytogenetics. Conclusion: Our results indicate that cytomorphology and classification according to FAB criteria are still necessary for the diagnosis of AML but have no relevance for prognosis in addition to cytogenetics. Our results suggest that the WHO classification should be further developed by using cytogenetics as the main determinant of biology. Dysplastic features, in particular, have no additional impact on predicting prognosis when cytogenetics are taken into account.

scholarly journals A Curious Novel Combination of Nucleophosmin (NPM1) Gene Mutations Leading to Aberrant Cytoplasmic Dislocation of NPM1 in Acute Myeloid Leukemia (AML)

Genes ◽  
2021 ◽  
Vol 12 (9) ◽  
pp. 1426
Author(s):  
Alessandra Venanzi ◽  
Roberta Rossi ◽  
Giovanni Martino ◽  
Ombretta Annibali ◽  
Giuseppe Avvisati ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Nuclear Export ◽  
Myeloid Leukemia ◽  
Nuclear Export Signal ◽  
Gene Mutations ◽  
Molecular Alteration ◽  
C Terminus ◽  
Molecular Sequencing ◽  
Acute Myeloid

Nucleophosmin (NPM1) mutations occurring in acute myeloid leukemia (AML) (about 50 so far identified) cluster almost exclusively in exon 12 and lead to common changes at the NPM1 mutants C-terminus, i.e., loss of tryptophans 288 and 290 (or 290 alone) and creation of a new nuclear export signal (NES), at the bases of exportin-1(XPO1)-mediated aberrant cytoplasmic NPM1. Immunohistochemistry (IHC) detects cytoplasmic NPM1 and is predictive of the molecular alteration. Besides IHC and molecular sequencing, Western blotting (WB) with anti-NPM1 mutant specific antibodies is another approach to identify NPM1-mutated AML. Here, we show that among 382 AML cases with NPM1 exon 12 mutations, one was not recognized by WB, and describe the discovery of a novel combination of two mutations involving exon 12. This appeared as a conventional mutation A with the known TCTG nucleotides insertion/duplication accompanied by a second event (i.e., an 8-nucleotide deletion occurring 15 nucleotides downstream of the TCTG insertion), resulting in a new C-terminal protein sequence. Strikingly, the sequence included a functional NES ensuring cytoplasmic relocation of the new mutant supporting the role of cytoplasmic NPM1 as critical in AML leukemogenesis.

scholarly journals Genetic Factors in Acute Myeloid Leukemia With Myelodysplasia-Related Changes

2020 ◽  
Vol 153 (5) ◽  
pp. 656-663 ◽  
Author(s):  
Hong Fang ◽  
Rong He ◽  
April Chiu ◽  
David S Viswanatha ◽  
Rhett P Ketterling ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Genetic Factors ◽  
Myeloproliferative Neoplasm ◽  
World Health ◽  
Genetic Profile ◽  
Cytogenetic Abnormalities ◽  
History Of ◽  
Health Organization ◽  
Acute Myeloid

Abstract Objectives Acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) is a heterogeneous category with a broad range of underlying genetic abnormalities. We investigated the significance of genetic factors in a large series of AML-MRC cases. Methods The morphologic findings, genetic data, and patient outcomes were assessed in 186 AML-MRC cases. Results The median overall survival (OS) was dismal in AML-MRC patients (median, 7.6 months; 95% confidence interval, 5-10.6 months). Karyotypically normal cases and cytogenetically abnormal cases without myelodysplastic syndrome (MDS)-related cytogenetic abnormalities showed similar OS, significantly better than cases carrying MDS-related cytogenetic abnormalities. MDS-related cytogenetic abnormalities, monosomal or complex karyotype, and history of MDS or myelodysplastic/myeloproliferative neoplasm were all associated with dismal outcome. Conclusions AML-MRC predicts a poor prognosis. Our study supports the finding that the genetic profile plays a key role in determining prognosis in AML-MRC as defined according to the World Health Organization revised fourth edition (2017) diagnostic criteria.

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