GAS6 Oncogene and Reverse MLLT3-KMT2A Duplications in an Infant with Acute Myeloid Leukemia and a Novel Complex Hyperdiploid Karyotype: Detailed High-Resolution Molecular Cytogenetic Studies

2017 ◽  
Vol 152 (1) ◽  
pp. 33-37
Author(s):  
Roberto R. Capela de Matos ◽  
Daniela R. Ney Garcia ◽  
Elaine Cifoni ◽  
Moneeb A.K. Othman ◽  
Mariana Tavares de Souza ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Resolution ◽  
Myeloid Leukemia ◽  
Molecular Cytogenetic ◽  
Severe Diarrhea ◽  
Molecular Abnormalities ◽  
Cytogenetic Studies ◽  
Novel Complex ◽  
Ploidy Changes ◽  
Acute Myeloid

Pediatric acute myeloid leukemia (AML) is a highly heterogeneous disease, presenting cytogenetic and molecular abnormalities which turned out to be critical prognostic factors. Ploidy changes as gain or loss of individual chromosomes are rare in AML, occurring only in about 1-2% of the affected children. Hyperdiploid karyotypes are exceedingly rare in infants less than 12 months of age. In this age group, structural rearrangements involving the KMT2A gene occur in about 58% of the cases. Among them, the translocation t(9;11)(p22;q23), KMT2A-MLLT3, is the most common abnormality accounting for approximately 22% of KMT2A rearrangements in infant AML cases. Here, we describe a 7- month-old girl with a history of fever and severe diarrhea, and a physical examination remarkable for pallor and hepatosplenomegaly. A novel complex hyperdiploid karyotype 53,XX,+X,+6,t(9;11)(p21.3;q23.3),+der(9)t(9;11)(p21.3;q23.3),dup(13)(q31q34),+14,+19,+21,+22 was characterized by high-resolution molecular cytogenetic approaches. Fluorescence in situ hybridization, multiplex-FISH, and multicolor chromosome banding were applied, revealing 2 reverse MLLT3-KMT2A fusions and a duplication of the GAS6 oncogene. Our work suggests that molecular cytogenetic studies are crucial for the planning of a proper strategy for risk therapy in AML infants with hyperdiploid karyotypes.

scholarly journals Molecular cytogenetic studies characterizing a novel complex karyotype with an uncommon 5q22 deletion in childhood acute myeloid leukemia

2015 ◽  
Vol 8 (1) ◽  
Author(s):  
Amanda Faria de Figueiredo ◽  
Roberto Rodrigues Capela de Matos ◽  
Moneeb A. K. Othman ◽  
Thomas Liehr ◽  
Elaine Sobral da Costa ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Complex Karyotype ◽  
Molecular Cytogenetic ◽  
Cytogenetic Studies ◽  
Childhood Acute Myeloid Leukemia ◽  
Novel Complex ◽  
Acute Myeloid

How I treat acute myeloid leukemia

Blood ◽  
2010 ◽  
Vol 116 (17) ◽  
pp. 3147-3156 ◽  
Author(s):  
Jacob M. Rowe ◽  
Martin S. Tallman
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Allogeneic Transplantation ◽  
Malignant Cell ◽  
Current Approach ◽  
Molecular Abnormalities ◽  
The Past ◽  
Survival Pathways ◽  
Large Populations ◽  
Acute Myeloid

AbstractMore than one quarter of a million adults throughout the world are diagnosed annually with acute myeloid leukemia (AML). Despite considerable progress during the past 3 decades in the therapy of AML, two-thirds of young adults and 90% of older adults still die of their disease. The reported median age has increased over the past few decades, mostly because of a greater willingness of physicians to diagnose and treat older patients, and now is 72 years. The greatest challenge is in this age group. However, much improvement in therapy is needed for all adults with AML. Recent advances in allogeneic transplantation, a better understanding of prognostic factors, and development of targeted agents have only modestly improved overall outcome when large populations of patients are considered. Although an explosion in knowledge about the molecular pathogenesis of AML has outpaced treatment advances, such insights hold promise for the development of new therapies directed at specific molecular abnormalities that perturb malignant cell survival pathways. The current approach in 2010 to the management of this disease is presented through a discussion of illustrative cases.

scholarly journals MicroRNA signatures associated with cytogenetics and prognosis in acute myeloid leukemia

Blood ◽  
2008 ◽  
Vol 111 (6) ◽  
pp. 3183-3189 ◽  
Author(s):  
Ramiro Garzon ◽  
Stefano Volinia ◽  
Chang-Gong Liu ◽  
Cecilia Fernandez-Cymering ◽  
Tiziana Palumbo ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Mirna Expression ◽  
Myeloid Leukemia ◽  
Cox Regression ◽  
Independent Set ◽  
Microarray Platform ◽  
Small Subset ◽  
Trisomy 8 ◽  
Molecular Abnormalities ◽  
Acute Myeloid

Abstract MicroRNAs (miRNAs) are small RNAs of 19 to 25 nucleotides that are negative regulators of gene expression. To determine whether miRNAs are associated with cytogenetic abnormalities and clinical features in acute myeloid leukemia (AML), we evaluated the miRNA expression of CD34+ cells and 122 untreated adult AML cases using a microarray platform. After background subtraction and normalization using a set of housekeeping genes, data were analyzed using Significance Analysis of Microarrays. An independent set of 60 untreated AML patients was used to validate the outcome signatures using real-time polymerase chain reaction. We identified several miRNAs differentially expressed between CD34+ normal cells and the AML samples. miRNA expression was also closely associated with selected cytogenetic and molecular abnormalities, such as t(11q23), isolated trisomy 8, and FLT3-ITD mutations. Furthermore, patients with high expression of miR-191 and miR-199a had significantly worse overall and event-free survival than AML patients with low expression (overall survival: miR-191, P = .03; and miR-199a, P = .001, Cox regression). In conclusion, miRNA expression in AML is closely associated with cytogenetics and FLT3-ITD mutations. A small subset of miRNAs is correlated with survival.

Cytogenetic Studies in Patients with Acute Myeloid Leukemia Following a Myelodysplastic Syndrome

1991 ◽  
Vol 3 (5-6) ◽  
pp. 423-427 ◽  
Author(s):  
Hans Josef Weh ◽  
Rolf Kuse ◽  
Doris Seeger ◽  
Stefan Suciu ◽  
Dieter Kurt Hossfeld
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndrome ◽  
Myeloid Leukemia ◽  
Cytogenetic Studies ◽  
Acute Myeloid

Morphologic, immunologic and cytogenetic studies in acute myeloid leukemia following occupational exposure to pesticides and organic solvents

1992 ◽  
Vol 16 (8) ◽  
pp. 789-796 ◽  
Author(s):  
Antonio Cuneo ◽  
Franca Fagioli ◽  
Isabella Pazzi ◽  
Antonella Tallarico ◽  
Rita Previati ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Occupational Exposure ◽  
Organic Solvents ◽  
Myeloid Leukemia ◽  
Cytogenetic Studies ◽  
Acute Myeloid

Monocytic Maturation Induced by FLT3 Inhibitor Therapy of Acute Myeloid Leukemia: Morphologic and Immunophenotypic Characteristics

2019 ◽  
Vol 51 (5) ◽  
pp. 478-483
Author(s):  
Cade D Arries ◽  
Sophia L Yohe
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Cell Population ◽  
Myeloid Leukemia ◽  
Inhibitor Therapy ◽  
Molecular Abnormalities ◽  
Flt3 Inhibitor ◽  
Flt3 Inhibitors ◽  
Acute Myeloid

Abstract Background FMS-like tyrosine kinase-3 (FLT3-ITD) mutations are some of the most common mutations in acute myeloid leukemia (AML), and patient outcomes have improved since the advent of tyrosine kinase inhibitors. First, granulocytic differentiation was described in FLT3-positive AML treated with FLT3 inhibitors, and more recently, monocytic differentiation was reported. Methods Two patients with myelomonocytic cells in their bone marrow were identified during routine follow-up after AML treatment that included FLT3 inhibitors. The bone marrow study was done as standard of care. Results Both patients had FLT3-ITD+ AML and showed an atypical maturing monocytic cell population and a decrease in the leukemic blast cell population after FLT3 inhibitor therapy. Concurrent genetic testing revealed persistent genetic abnormalities. Conclusions These cases illustrate monocytic maturation in FLT3+ AML after FLT3 inhibitor treatment. It is critical for pathologists and clinicians to be aware of the differentiation phenomenon, as these patients have persistent molecular abnormalities despite response to treatment and normalization of blast counts.

Parallel Analyses Disclose Novel Genomic Imbalances in Acute Myeloid Leukemia with Complex Karyotypes.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2357-2357
Author(s):  
Frank G. Rucker ◽  
Lars Bullinger ◽  
Hans A. Kestler ◽  
Peter Lichter ◽  
Konstanze Dohner ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
High Resolution ◽  
Candidate Genes ◽  
Myeloid Leukemia ◽  
Parallel Analysis ◽  
Genomic Imbalances ◽  
Genome Wide ◽  
Genomic Regions ◽  
Acute Myeloid

Abstract Approximately 10 to 15 % of acute myeloid leukemia (AML) cases exhibit complex karyotypes, i.e., three or more chromosome abnormalities without presence of a specific fusion transcript. To identify novel genomic regions of interest in AML with complex karyotypes we applied comparative genomic hybridization to microarrays (matrix-CGH) allowing high-resolution genome-wide screening of genomic imbalances. We designed a microarray consisting of 2799 different BAC- or PAC-vectors. A set of 1500 of these clones covers the whole human genome with a physical distance of approximately 1.5 Mb. The remaining 1299 clones either contiguously span genomic regions known to be frequently involved in hematologic malignancies (e.g., 1p, 2p, 3q, 7q, 9p, 11q, 12q, 13q, 17p, 18q) (n=600) or contain oncogenes or tumor suppressor genes (n=699). Using this microarray platform, 83 AML cases with complex karyotypes were analyzed. Genomic losses were found more frequently than gains; the most frequent losses were deletions of 5q (71%), 17p (53%), 7q (48%); followed by deletions of 18q (30%), 16q (28%), 3p and 12q (20% each), 12p (18%), 20q (17%), and 11q (12%). The most frequent genomic gains were trisomies of 11q (39%) and 8q (31%); followed by trisomies of 1p (22%), 21q (20%), 9p (14%), 22q (13%), 13q (12%), and 6p (10%). In part, some critical segments were delineated to genomic fragments of 0.8 to a few megabase pairs in size. In lost/gained regions parallel analysis of gene expression using microarray technology detected a gene dosage effect with significant lower/higher average gene expression levels across the genes located in the respective regions. Furthermore, 47 high-level DNA amplifications in 19 different regions were identified; amplifications occurring in at least two cases mapped to (candidate genes in the amplicon) 11q23.3-q24.1 (n=10; ETS, FLI1); 11q23.3 (n=8; MLL, DDX6); 21q22 (n=5; ERG, ETS2); 13q12 (n=3; CDX2, FLT1, FLT3, PAN3); 8q24 (n=3; C8FW, MYC); 9p24 (n=2; JAK2); 12p13 (n=2; FGF6, CCND2); and 20q11 (n=2; ID1, BCL2L1). Parallel analysis displayed overexpressed candidate genes in critical amplified region, e.g., C8FW and MYC in 8q24. In conclusion, using high-resolution genome-wide screening tools such as matrix-CGH allows to unravel the enormous genetic diversity of AML cases with complex karyotypes, and correlation with global gene expression studies facilitates the delineation of disease-related candidate genes located in the critical regions.

Treatment for Primary Acute Myeloid Leukemia: Results of Two Consecutive Trials From the Spanish CETLAM Group Showing Improvement with the Use of G-CSF Priming and Precise Risk-Adapted Therapy.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1066-1066
Author(s):  
Jorge Sierra ◽  
Montserrat Hoyos ◽  
Josep F. Nomdedeu ◽  
Jordi Esteve ◽  
Rafael F. Duarte ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Adult Patients ◽  
High Dose ◽  
Phase Ii Trials ◽  
Molecular Abnormalities ◽  
Factors Influencing ◽  
Leukocyte Counts ◽  
Postremission Therapy ◽  
Acute Myeloid

Abstract Abstract 1066 Different approaches have been investigated to improve the prognosis of adult patients with primary acute myeloid leukemia. In two consecutive phase II trials our group has explored the use of intermediate-dose cytarabine in induction associated with idarubicin and etoposide, the addition of G-CSF priming to the previous combination, and risk-adapted postremission therapy. Objective: To compare the results of two consecutive trials for primary AML and to analyze the factors influencing the outcome. Patients and methods: Adult patients between 17 and 60 years of age with de novo AML, diagnosed between 1999 and 2009, were included in the CETLAM AML-99 and AML-03 trials. Induction chemotherapy (CT) included one or two courses of idarubicin 12 mg/m2 IV days 1,3,5, cytarabine 500 mg/m2/12h over 2h IV days 1,3,5,7 and etoposide 100 mg/m2 IV days 1,2,3. This was followed by one consolidation with mitoxantrone 12 mg/m2 IV from day 4 to 6, and cytarabine 500 mg/m2/12h IV from day 1–6. In the AML 03 trial, patients also received G-CSF priming, 150 mg/m2 subcutaneously (SC) from day 0 to the last day of induction and consolidation CT. Postremission therapy consisted of high-dose cytarabine (CBF AML), autologous or allogeneic hematopoietic transplantation depending on cytogenetics, courses to complete remission (CR), and in the AML-03 protocol also based on molecular abnormalities involving FLT3 or MLL genes and/or the persistence of minimal residual disease after consolidation. Results: Overall, 788 patients were included, 353 in the AML-99 trial and 435 in the AML-03. Median age of the patients was 46 years (range 17–60). There were no differences between patients included in the two protocols regarding age, gender, leukocyte counts, cytogenetics and proportion of favourable and unfavourable molecular cases in the group with intermediate-risk karyotype. The main results achieved appear in the table. Multivariate analysis confirmed the favourable impact of AML-03 protocol on outcome. Other significant factors influencing survival were age, leukocyte counts and cytogenetics. Conclusion: G-CSF priming improved the CR rate of adult patients with primary AML and favourable or unfavourable cytogenetics. This fact and a more precise risk-adapted therapy taking into account genetic data and MRD studies translated into improved overall survival. Disclosures: No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document