scholarly journals Molecular Genetic Testing for Acute Myeloid Leukemia

2016 ◽  
Vol 29 (6) ◽  
pp. 411-418 ◽  
Author(s):  
Veronika Janečková ◽  
Lukáš Semerád ◽  
Ivana Ježíšková ◽  
Dana Dvořáková ◽  
Martin Čulen ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Genetic Testing ◽  
Myeloid Leukemia ◽  
Molecular Genetic ◽  
Molecular Genetic Testing ◽  
Acute Myeloid

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.

scholarly journals Clonal hematopoiesis and measurable residual disease assessment in acute myeloid leukemia

Blood ◽  
2020 ◽  
Vol 135 (20) ◽  
pp. 1729-1738 ◽  
Author(s):  
Robert P. Hasserjian ◽  
David P. Steensma ◽  
Timothy A. Graubert ◽  
Benjamin L. Ebert
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Hematopoietic Cell Transplantation ◽  
Residual Disease ◽  
Molecular Genetic ◽  
Disease Assessment ◽  
Clonal Hematopoiesis ◽  
Myeloid Neoplasm ◽  
Measurable Residual Disease ◽  
Acute Myeloid

Abstract Current objectives regarding treatment of acute myeloid leukemia (AML) include achieving complete remission (CR) by clinicopathological criteria followed by interrogation for the presence of minimal/measurable residual disease (MRD) by molecular genetic and/or flow cytometric techniques. Although advances in molecular genetic technologies have enabled highly sensitive detection of AML-associated mutations and translocations, determination of MRD is complicated by the fact that many treated patients have persistent clonal hematopoiesis (CH) that may not reflect residual AML. CH detected in AML patients in CR includes true residual or early recurrent AML, myelodysplastic syndrome or CH that is ancestral to the AML, and independent or newly emerging clones of uncertain leukemogenic potential. Although the presence of AML-related mutations has been shown to be a harbinger of relapse in multiple studies, the significance of other types of CH is less well understood. In patients who undergo allogeneic hematopoietic cell transplantation (HCT), post-HCT clones can be donor-derived and in some cases engender a new myeloid neoplasm that is clonally unrelated to the recipient’s original AML. In this article, we discuss the spectrum of CH that can be detected in treated AML patients, propose terminology to standardize nomenclature in this setting, and review clinical data and areas of uncertainty among the various types of posttreatment hematopoietic clones.

Genetic and immunophenotypical diagnostics for acute myeloid leukemia and their implication on treatment strategy

2012 ◽  
Vol 0 (0) ◽  
pp. -
Author(s):  
Sabine Kayser ◽  
Richard F. Schlenk
Keyword(s):  
Acute Myeloid Leukemia ◽  
Treatment Strategy ◽  
Myeloid Leukemia ◽  
Molecular Genetic ◽  
Treatment Strategies ◽  
Disease Classification ◽  
Novel Drugs ◽  
Genetic Abnormalities ◽  
Binding Factor ◽  
Acute Myeloid

AbstractCytogenetic and molecular genetic abnormalities in acute myeloid leukemia (AML) play an important role in the pathogenesis, are absolutely necessary for disease classification, are the most important prognostic factors for induction success and survival, and are increasingly used for specific genotype-adapted treatment approaches. In particular, molecular-targeted treatment strategies are evolving within clinical trials in the AML entities core-binding factor AML, characterized by t(8;21) and inv(16)/t(16;16), and AML with mutated NPM1, as well as AML with an internal tandem duplication of the FMS-related tyrosine kinase 3 (FLT3) gene. The link between the leukemogenic importance of genetic abnormalities and their role as a potential target for well-known and novel drugs will contribute to the stepwise replacement of purely risk-adapted therapy to a more and more genotype-adapted treatment strategy.

scholarly journals Hyperbasophilic Variant of Acute Promyelocytic Leukemia

2016 ◽  
Vol 3 (2) ◽  
pp. 125
Author(s):  
Preeti Bajaj ◽  
Rajyaguru Devangana ◽  
B. S. Shah ◽  
Amrinder Kaur
Keyword(s):  
Acute Myeloid Leukemia ◽  
Acute Promyelocytic Leukemia ◽  
Myeloid Leukemia ◽  
Molecular Genetic ◽  
Chromosomal Translocation ◽  
Promyelocytic Leukemia ◽  
Chromosome 17 ◽  
Chromosome 15 ◽  
Chromosome 11 ◽  
Acute Myeloid

Acute Promyelocytic Leukemia (APL) is an extremely rare variant of acute myeloid leukemia. APL constitutes around 10-15 % of acute myeloid leukemia in adults. It is commonly diagnosed around 40 years age. Molecular/genetic studies exhibit chromosomal translocation between chromosome 15 and chromosome 17-t(15;17)(q22;q21) and PML-RARa rearrangement. Four variants of APL have been identified: The classic form M<sub>3</sub> hypergranular variant, the microgranular variant, the hyperbasophilic form and zinc-finger form-M<sub>3</sub>r, identified by a different chromosomal translocation, between chromosome 11 and chromosome 17:t(11,17) (q23, q11-12).

scholarly journals Acute myeloid leukemia mmicking an Ewing’s sarcoma family tumor: A clinical case

2021 ◽  
Vol 58 (4) ◽  
pp. 24-28
Author(s):  
S. BAITUROVA ◽  
K. OMAROVA ◽  
R. BORANBAEVA ◽  
G. ABDILOVA ◽  
O. PANKOVA ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Clinical Case ◽  
Soft Tissues ◽  
Ewing’S Sarcoma ◽  
Ewing's Sarcoma ◽  
Molecular Genetic ◽  
Young Patients ◽  
Genetic Studies ◽  
Acute Myeloid

Relevance: M6 variant of acute myeloid leukemia is extremely rare in pediatric practice. The diverse clinical manifestations of erythroid leukemia complicate the timely diagnosis of this group of diseases. Purpose: to describe a clinical case of congenital erythroid leukemia with multiple lesions of soft tissues and the skeletal system with complications in the form of the convulsive disorder, presented as a tumor of the Ewing’s sarcoma family, diagnosed at the Research Center of Pediatrics and Pediatric Surgery (Almaty, the Republic of Kazakhstan). Results: The presented clinical case demonstrated challenges in diagnosing and treating young patients with multiple life-threatening tumor lesions. The need to develop molecular genetic studies and expand diagnostic capabilities is an integral part of treating oncohematological diseases. Conclusion: The presented clinical case is of great interest due to its rareness. This case confirms the need to conduct all diagnostic manipulations to assess the process prevalence and choose and conduct molecular genetic studies on all examination and treatment stages.

scholarly journals Loss of H3K27 Methylation Identifies Poor Outcome in Adult-Onset Acute Myeloid Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 24-24
Author(s):  
Anneke D. van Dijk ◽  
Fieke W Hoff ◽  
Yihua Qiu ◽  
Eveline S. de Bont ◽  
Sophia W.M. Bruggeman ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Molecular Genetic ◽  
Functional Enrichment ◽  
Prognostic Impact ◽  
Cox Regression Analysis ◽  
H3k27 Methylation ◽  
Acute Myeloid

Background: Acute myeloid leukemia (AML) is an epigenetically heterogeneous disease. The intensity of treatment is currently guided by cytogenetic and molecular genetic risk classifications; however these incompletely predict outcomes, requiring additional information for more accurate predictions. We aimed to identify potential prognostic implications of epigenetic modification of histone proteins, with a focus of H3K27 methylation in relation to mutations in chromatin, splicing and transcriptional regulators. Material and methods: Histone methylation mark expressions were evaluated in a cohort of 241 AML bone marrow (BM) and peripheral blood (PB) samples from patients admitted at the MD Anderson Cancer Center relative to their expression in CD34+ BM derived samples from healthy donors. Simultaneous analysis of 230 proteins was performed using the reverse phase protein array - a high-throughput, quantitative proteomic platform that enables identification of aberrant expressed proteins and the pathways they act in. Additional mutational analysis was performed on 65 BM samples. Results:H3K27Me3 was significantly lower in both BM and PB leukemic-derived samples compared to their expression in normal BM (figure 1A). A greater loss of H3K27Me3 associated with increased proliferative potential and shorter overall survival (OS) in the whole patient population (n=241, HR=0.64, 95% CI=0.47-0.87, p&lt;0.01), as well as in subsets, e.g. cytogenetically normal AML (n=110, HR=0.62, 95% CI=0.40-0.97, p=0.03). To study the prognostic impact of H3K27Me3 in the context of cytogenetic aberrations and mutations, multivariate cox regression analysis was performed which identified H3K27Me3 level as an independent favorable prognostic factor in all (HR=0.74, 95%CI=0.57-0.95, p=0.02) as well as in P53 mutated AML (n=54, HR=0.48, 95%CI=0.26-0.87, p=0.02). A total of 78 AML patients had molecular data available for the major methylation affecting genes, i.e. IDH1, IDH2, DNMT3A and TET2. The level of H3K27Me3 was not prognostic in patients without any DNA methylation affecting mutation present, but patients with at least one mutation in any of these had better outcome when H3K27Me3 levels were high (highest tertile, figure 1A) compared to those with lower levels (median OS 7.1 vs. 24.1 months, HR=0.42, 95% CI=0.21-0.83, p=0.01, figure 1B). Mutations in U2AF1 and SRSF2 affect the spliceosome and are frequently found in antecedent hematological disorders (AHD), as well as are mutations in chromatin regulating genes ASXL1 and BCOR. We observed significant decreased H3K27Me3 in patients with these mutations corresponding with observed lower levels of H3K27Me3 in patients with AHD than those without (p=0.035). BCOR, SRSF2, U2AF1 and ASXL1 mutations confer poor prognosis in myeloid malignancies, however, in our cohort of 65 sequenced AML patients; not individual or a combination of these mutations were independent prognostic factors, but the degree of H3K27Me3 in these patients (HR= 0.49, 95% CI=0.25-0.95, p=0.03). To recognize dysregulated pathways in AML patients with the identified loss of H3K27Me3, we examined correlations of H3K27Me3 with the other 229 proteins on the array. H3K27Me3 is catalyzed by the polycomb group protein EZH2 and is linked to transcriptional repression via the formation of heterochromatin regions. To identify upregulated proteins and pathways upon the loss of H3K27Me3, we focused on significant negatively correlated proteins with H3K27Me3 leading us to the identification of 20 total and 6 phospho-proteins that showed increased expression upon decreased H3K27Me3. Functional enrichment analysis of this protein set revealed an upregulated anti-apoptotic phenotype. Conclusion:This study shows that proteomic profiling of epigenetic modifications on the histone level have clinical implications in AML and support the idea that epigenetic patterns contribute to a more accurate picture of the leukemic state complementing cytogenetic and molecular genetic subgrouping. Figure 1. A) Lower H3K27Me3 in BM and PB derived AML samples compared to normal CD34+. **** represents p&lt;0.0001, ns = not significant. B) Overall survival probability in AML patients with any DNA methylation affecting mutation (i.e. IDH1/2, DNMT3A, TET2, n=53) according to H3K27Me3 low (blue) and high (orange) status. Figure 1 Disclosures No relevant conflicts of interest to declare.

Differences in Cyto- and Molecular Genetic Abnormalities between Children <2 Years and Older Children with Acute Myeloid Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1830-1830
Author(s):  
Brian V. Balgobind ◽  
Iris H. Hollink ◽  
Dirk Reinhardt ◽  
Jutta Bradtke ◽  
Andrea Teigler-Schlegel ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Young Children ◽  
Myeloid Leukemia ◽  
Molecular Genetic ◽  
Age Groups ◽  
Normal Karyotype ◽  
Older Children ◽  
Ras Mutations ◽  
Genetic Abnormalities ◽  
Acute Myeloid

Abstract Young children (defined as &lt;2 years old) with acute myeloid leukemia (AML) do not differ in outcome when compared with older children with AML. Previously, distinct cytogenetic aberrations specific for AML in young children have been reported, such as t(7;12), and t(1;22), which is found exclusively in FAB M7. Moreover, young children with AML are characterized by a high frequency of 11q23-rearrangements. However, so far, no information is available on differences in the molecular genetic background of these two age groups. We therefore retrospectively investigated the distribution of different cytogenetic and molecular aberrations in a large cohort (n=435) of pediatric AML cases, of which 75 (17%) were young children. The predominant cytogenetic aberration in infant AML consisted of 11q23-rearrangements, which occurred in 44% of young children versus 17% in older children (p=&lt;0.005), without differences in the distribution of 11q23-translocation partners. We also found significant differences in other cytogenetic subgroups of AML between young and older children, i.e. normal karyotype, 5% vs. 18%, respectively (p=0.008) and complex karyotype, 12% vs. 5% (p=0.03). t(7;12) (n=3) and t(8;16) (n=3) were only detected in young children, in contrast to t(15;17) (n=16) and t(8;21) (n=44), which were only seen in older children. Patients were also screened for molecular abnormalities, including the mutational hotspots of c-KIT (n=229), FLT3 (n=230), N-RAS (n=187), K-RAS (n=187), PTPN11 (n=216), MLL-partial tandem duplications (MLL-PTD) (n=240) and NPM1 (n=291). In the overall cohort, a significantly different age distribution was found for NPM1 mutations (0% young vs. 9% in older children; p=0.05) and FLT3-ITD (0% vs. 21%, respectively; p=0.005). Mutations in the other genes showed no clear correlation with age. Several non-random associations between molecular and cytogenetic abnormalities were detected. 89% of c-KIT mutations were associated with core-binding factor AML in children ≥2 years old. In young children, 2/4 c-KIT-mutated cases were associated with an MLL-rearrangement. NPM1 and FLT3-ITD mutations in older children were significantly correlated with normal karyotype AML (57% of NPM1 mutations, and 75% of FLT3/ITD; p=&lt;0.005). In young children, 71% of RAS mutations were associated with an 11q23-rearrangement vs. 28% in older children (p=0.08). In older children however, 41% of the RAS mutations were associated with a normal karyotype. These data suggest that young children with AML are characterized by differences in the type and frequency of cytogenetic and molecular genetic abnormalities when compared with older children with AML, possibly reflecting differences in underlying biology between these age-groups. These differences may become clinically relevant in the era of molecularly targeted therapy.

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