scholarly journals Case of Patient with AML with Complex Karyotype including Ultra-Rare t(4;8)(q32;q13), t(4;11)(q21;p15) and Familial Aggregation of Myeloid Malignancies

Medicina ◽  
2022 ◽  
Vol 58 (1) ◽  
pp. 105
Author(s):  
Sławomir Milczarek ◽  
Ewa Studniak ◽  
Bartłomiej Baumert ◽  
Michał Janowski ◽  
Wioleta Bonda ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Familial Aggregation ◽  
Subsequent Generation ◽  
Complex Karyotype ◽  
Unique Case ◽  
Interesting Issue ◽  
Myeloid Malignancies ◽  
Gene Testing ◽  
Myeloid Leukemias ◽  
Acute Myeloid

We present a unique case of a young woman with acute myeloid leukemia (AML) with complex karyotype. The presence of the t(4;11)(q23;p15) is extremely rare in myeloid leukemias, while t(4;8)(q32;q13) has not yet been described in any leukemia reference. Another interesting issue is the familial aggregation of myeloid malignancies and worse course of the disease in each subsequent generation, as well as an earlier onset of the disease. Our report emphasizes the need for thorough pedigree examination upon myeloid malignancy diagnosis as there are relatives for whom counseling, gene testing, and surveillance may be highly advisable.

scholarly journals Familial Aggregation of Acute Myeloid Leukemia and Myelodysplastic Syndromes

2012 ◽  
Vol 30 (2) ◽  
pp. 179-183 ◽  
Author(s):  
Lynn R. Goldin ◽  
Sigurdur Y. Kristinsson ◽  
Xueying Sharon Liang ◽  
Åsa R. Derolf ◽  
Ola Landgren ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndromes ◽  
Myeloid Leukemia ◽  
Myeloproliferative Neoplasms ◽  
Familial Aggregation ◽  
Young Patients ◽  
Myeloid Malignancies ◽  
First Degree Relatives ◽  
Increased Risk ◽  
Acute Myeloid

Purpose Apart from rare pedigrees with multiple cases of acute myeloid leukemia (AML), there is limited data on familial aggregation of AML and myelodysplastic syndromes (MDSs) in the population. Patients and Methods Swedish population-based registry data were used to evaluate risk of AML, MDS, and other malignancies among 24,573 first-degree relatives of 6,962 patients with AML and 1,388 patients with MDS compared with 106,224 first-degree relatives of matched controls. We used a marginal survival model to calculate familial aggregation. Results AML and/or MDS did not aggregate significantly in relatives of patients with AML. There was a modest risk ratio (RR, 1.3; 95% CI, 0.9 to 1.8) in myeloproliferative/myeloid malignancies combined. The risks for any hematologic or any solid tumor were modestly but significantly increased. Relatives of patients with MDS did not show an increased risk for any hematologic tumors. In contrast, we found a significantly increased risk (RR, 6.5; 95% CI, 1.1 to 38.0) of AML/MDS and of all myeloid malignancies combined (RR, 3.1; 95% CI, 1.0 to 9.8) among relatives of patients diagnosed at younger than age 21 years. Conclusion We did not find evidence for familial aggregation of the severe end of the spectrum of myeloid malignancies (AML and MDS). The risks of myeloproliferative neoplasms were modestly increased with trends toward significance, suggesting a possible role of inheritance. In contrast, although limited in sample size, relatives of young patients with AML were at increased risk of AML/MDS, suggesting that germline genes may play a stronger role in these patients. The increased risk of all hematologic malignancies and of solid tumors among relatives of patients with AML suggests that genes for malignancy in general and/or other environmental factors may be shared.

scholarly journals The HACE1-NRF2 Axis a Novel Target in Acute Myeloid Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5132-5132
Author(s):  
Andoni Garitano-Trojaola ◽  
Eva Teufel ◽  
Nadine Rodhes ◽  
Jennifer Kreckel ◽  
Thorsten Stuehmer ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Protein Expression ◽  
Cell Viability ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
U937 Cells ◽  
Myeloid Malignancies ◽  
Myeloid Leukemias ◽  
Novel Target ◽  
Acute Myeloid

Abstract Acute Myeloid Leukemia (AML) is a genetically heterogenous disease characterized by clonal expansion of immature myeloid progenitors cells in the bone marrow (BM). Despite this genetic heterogeneity, AML patients share Leukemia associated oncogenes such as NF-E2-related factor 2 (Nrf2) (Rushworth SA et al.). NRF2 is a transcription factor that activates genes with antioxidant response elements (ARE)-containing promoters and protects cancer cells from apoptosis. Inhibition of NRF2 or antioxidant defense increases the level of Radical Oxygen Species (ROS), leading to tumor supression (Chio IIC et al.). Recently, the E3 Ubiquitin-Protein Ligase HACE1, a tumor suppressor in solid tumors, was demonstrated to promote the expression of NRF2 in Huntigton disease (Rotblat B et al.). Thus, we hypothesized a role for HACE1 as an oncogenic factor acting through NRF2 activation in myeloid malignancies and provide first data supporting the HACE1-NRF2 axis to be a novel target in acute myeloid leukemias. Material and methods The mRNA expression data from AML patients (296 samples) vs normal Hematopoietic Stem Cells (HSC) (6 samples) were exported from the bloodSpot database. HACE1 mRNA and protein expression was measured by q-RT-PCR and western blot in 12 commercially available Myeloid Malignancies cell lines. The HACE1 inducible knock down (KD) was carried out by Sleeping Beauty Transposon system in U937 and NOMO-1 cell lines. The cell viability was analyzed by Cell Titer Glo Luminescent assay. Apoptosis was measured by Annexin V (AV)/Propidium Iodide (PI) assay. Results and discussion HACE1 mRNA is downregulated in AML patients compared to HSC (***p<0.001, Bloodspot database). However mRNA and HACE1 protein expression do not correlate in AML cell lines, suggesting post translational modifications. High HACE1 protein expression was observed in most AML cell lines. HACE1 KD reduced drastically the cell viability of U937 cells through caspase activation and NRF2 degradation. However, no effect on cell viability was observed in NOMO-1 cells. Recently, non-programmed cell death necroptosis induction has been described by TNFR1 activation in HACE1 knock out Mouse Embrionic Fibroblast cells (Tortola L et al.). In line with this study, we observed that TNF induces strong cell death in HACE1 KD NOMO-1 cells within 48 hours. In addition HACE1 KD promotes autophagy through p62 degradation (late autophagy marker) in U937 cells. Autophagy has recently been described to contribute to the differentiation and death of AML cells, and to the promotion of immunostimulatory signals activating immune responses against cancer cells (Chen L et al.; Pietrocola F et al.). Thus HACE1 might be a potential target to induce autophagy, providing a novel therapeutical target in the treatment of myeloid malignancies. Finally, HACE1 KD in our hands promoted sensitization of U937 and NOMO-1 cells to cytatarabine, the backbone therapy in AML patients. This treatment promotes HACE1 protein expression at 24 and 48 hours in NOMO-1 cells, which may explain the better response rates of HACE1 KD cells to cytarabine. Taken together, we provide first evidence of HACE1 being a novel oncogene in AML and that the HACE1-NRF2 axis is a promising target in the treatment of Acute Myeloid Leukemias. Disclosures Haferlach: MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

scholarly journals Asxl1 C-terminal mutation perturbs neutrophil differentiation in zebrafish

Leukemia ◽  
2021 ◽  
Author(s):  
Xiao Fang ◽  
Song’en Xu ◽  
Yiyue Zhang ◽  
Jin Xu ◽  
Zhibin Huang ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Chronic Myelomonocytic Leukemia ◽  
Nonsense Mutations ◽  
Myeloid Malignancies ◽  
A Subunit ◽  
Neutrophil Differentiation ◽  
Polycomb Repressive Complex 1 ◽  
Myelomonocytic Leukemia ◽  
Inhibitor Treatment ◽  
Acute Myeloid

AbstractASXL1 is one of the most frequently mutated genes in malignant myeloid diseases. In patients with myeloid malignancies, ASXL1 mutations are usually heterozygous frameshift or nonsense mutations leading to C-terminal truncation. Current disease models have predominantly total loss of ASXL1 or overexpressed C-terminal truncations. These models cannot fully recapitulate leukemogenesis and disease progression. We generated an endogenous C-terminal-truncated Asxl1 mutant in zebrafish that mimics human myeloid malignancies. At the embryonic stage, neutrophil differentiation was explicitly blocked. At 6 months, mutants initially exhibited a myelodysplastic syndrome-like phenotype with neutrophilic dysplasia. At 1 year, about 13% of mutants further acquired the phenotype of monocytosis, which mimics chronic myelomonocytic leukemia, or increased progenitors, which mimics acute myeloid leukemia. These features are comparable to myeloid malignancy progression in humans. Furthermore, transcriptome analysis, inhibitor treatment, and rescue assays indicated that asxl1-induced neutrophilic dysplasia was associated with reduced expression of bmi1a, a subunit of polycomb repressive complex 1 and a reported myeloid leukemia-associated gene. Our model demonstrated that neutrophilic dysplasia caused by asxl1 mutation is a foundation for the progression of myeloid malignancies, and illustrated a possible effect of the Asxl1-Bmi1a axis on regulating neutrophil development.

scholarly journals Database-Guided Analysis for Immunophenotypic Diagnosis and Follow-Up of Acute Myeloid Leukemia With Recurrent Genetic Abnormalities

2021 ◽  
Vol 11 ◽  
Author(s):  
Carmen-Mariana Aanei ◽  
Richard Veyrat-Masson ◽  
Cristina Selicean ◽  
Mirela Marian ◽  
Lauren Rigollet ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Residual Disease ◽  
Hematologic Malignancies ◽  
Multicolor Flow Cytometry ◽  
Phenotypic Differences ◽  
Molecular Tests ◽  
Genetic Abnormalities ◽  
Myeloid Leukemias ◽  
Acute Myeloid

Acute myeloid leukemias (AMLs) are hematologic malignancies with varied molecular and immunophenotypic profiles, making them difficult to diagnose and classify. High-dimensional analysis algorithms might increase the utility of multicolor flow cytometry for AML diagnosis and follow-up. The objective of the present study was to assess whether a Compass database-guided analysis can be used to achieve rapid and accurate diagnoses. We conducted this study to determine whether this method could be employed to pilote the genetic and molecular tests and to objectively identify different-from-normal (DfN) patterns to improve measurable residual disease follow-up in AML. Three Compass databases were built using Infinicyt 2.0 software, including normal myeloid-committed hematopoietic precursors (n = 20) and AML blasts harboring the most frequent recurrent genetic abnormalities (n = 50). The diagnostic accuracy of the Compass database-guided analysis was evaluated in a prospective validation study (125 suspected AML patients). This method excluded AML associated with the following genetic abnormalities: t(8;21), t(15;17), inv(16), and KMT2A translocation, with 92% sensitivity [95% confidence interval (CI): 78.6%–98.3%] and a 98.5% negative predictive value (95% CI: 90.6%–99.8%). Our data showed that the Compass database-guided analysis could identify phenotypic differences between AML groups, representing a useful tool for the identification of DfN patterns.

Association of the type of 5q loss with complex karyotype, clonal evolution,TP53mutation status, and prognosis in acute myeloid leukemia and myelodysplastic syndrome

2014 ◽  
Vol 53 (5) ◽  
pp. 402-410 ◽  
Author(s):  
Sarah Volkert ◽  
Alexander Kohlmann ◽  
Susanne Schnittger ◽  
Wolfgang Kern ◽  
Torsten Haferlach ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndrome ◽  
Myeloid Leukemia ◽  
Clonal Evolution ◽  
Complex Karyotype ◽  
Acute Myeloid

High frequency of dicentric chromosomes detected by multi-centromeric FISH in patients with acute myeloid leukemia and complex karyotype

2018 ◽  
Vol 68 ◽  
pp. 85-89 ◽  
Author(s):  
Iveta Sarova ◽  
Jana Brezinova ◽  
Zuzana Zemanova ◽  
Sarka Ransdorfova ◽  
Karla Svobodova ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Frequency ◽  
Myeloid Leukemia ◽  
Complex Karyotype ◽  
Dicentric Chromosomes ◽  
Acute Myeloid
Sign in / Sign up

Export Citation Format

Share Document