Loss of 17p is a major consequence of chromosomal translocations throughout the arm in hematologic malignancies (2023)

Der(5;17)(p10;q10) is a recurrent but rare aberration reported in myeloid neoplasia (MN). We report on 48 such patients, including 19 acute myeloid leukemia (AML) and 29 myelodysplastic syndrome (MDS), to characterize their clinicopathologic features. There were 29 males and 19 females, and the median age was 61 years (range: 18 to 80 years). 62.5% of patients had treatment-emergent disorders (t-MN), 70.8% had multilineage dysplasia, and 83.3% had complex karyotypes. In 39 patients, all FLT3, NPM1, CEBPA, and KIT mutations were wild-type, and isolated cases of NRAS, KRAS, IDH1, APC, and TET2 mutations were detected. TP53 mutations were identified in 8 out of 10 cases (80%). Median disease-free survival (DFS) and overall survival (OS) were 3 and 10 months, respectively, and did not differ between AML or MDS cases, or between de novo and treatment-emergent cases, or between groups with or without complex karyotypes. The 19 patients who achieved CR after chemotherapy and the 9 patients after stem cell transplantation had better overall survival (14 and 17.5 months, P=0.0128 and P=0.0086, respectively). Der(5;17)(p10;q10) represents a unique molecular cytogenetic subset in t-MNs and is associated with complex karyotypes. TP53 inactivation resulting from a 17p deletion combined with a TP53 mutation probably contributes to the poor clinical outcome in these patients.

Structural abnormalities of chromosome 7q have been regularly reported in B-cell chronic lymphoproliferative disorders. These include chromosomal translocations involving 7q21, leading to overexpression of the CDK6 gene. Three distinct translocations, t(7;14)(q21;q32), t(7;22)(q21;q11), and t(2;7)(p11;q21), result in assembly of the CDK6 gene with the immunoglobulin gene -enhancers during B-cell differentiation. In the last 2 years we have identified three patients with t(2;7)-associated lymphoproliferative neoplasm (p11;q21). Fluorescent in situ hybridization using the IGK probe and a library of bacterial artificial chromosome (BAC) clones located in bands 7q21.2 and 7q21.3 containing CDK6 revealed that the telomeric portion of the IGK probe moved to (7) region 51 kb upstream of the CDK6 transcription start site. To date, a total of 23 patients with indolent B-cell lymphoproliferative disorders and IG and CDK6 gene combinations have been reported, including 20 with IGK and CDK6 combinations. This rearrangement leads to overexpression of CDK6, which encodes a cyclin-dependent protein kinase involved in progression of the G1 phase of the cell cycle and the G1/S transition.

Translocations of chromosomes 1 and 15 are rare in hematological malignancies. To date, only 42 cases with t(1;15) have been reported as reciprocal or combined chromosomal abnormalities. We hereby report the first case to our knowledge of a 44-year-old woman with idiopathic thrombocythemia and severe myelofibrosis who developed acute myeloid leukemia (AML-M4) with the(1;15)(q10;q10). after 13 years of treatment. In addition, we reviewed the literature for all currently published cases with t(1;15).

Here we describe a novel unbalanced translocation of the entire der(3;10)(q10;q10) arm in a 58-year-old man with acute monocytic leukemia. The bone marrow was massively infiltrated with 22.2% monoblasts, 55.4% promonocytes and 5.6% monocytes. These monocytic cells were positive for myeloperoxidase and α-naphthylbutyrate esterase staining. Analysis of the surface markers revealed that they were positive for CD4, CD13, CD33, CD56 and HLA-DR but negative for CD14 and CD34. Chromosome analysis of bone marrow cells revealed 46,XY,+3,der(3;10)(q10;q10)[18]/46,XY[2]. The spectral karyotyping confirmed the (3;10)(q10;q10) as the only structural anomaly. Acquisition of normal chromosome 3 but not chromosome 10,(3;10)(q10;q10) resulted in trisomy 3q and monosomy 10p. +3,der(3;10)(q10;q10) is believed to play a key role in the pathogenesis of acute monocytic leukemia due to 3q gain or 10p loss.

This study describes the association of a derivative of chromosomal aberrations (1;18)(q10;q10) with essential thrombocythemia (ET) in a 75-year-old woman. Allele-specific polymerase chain reaction also revealed a V617F mutation in the Janus kinase 2 (JAK2) gene in the platelet compartment of this patient. The der(1;18)(q10;q10) anomaly has been previously reported in two cases of myeloid disease. The etiological impact of this combination of chromosomal abnormalities and JAK2 mutations on ET is still unclear. This is a new description of the abnormality of the derivative (1;18)(q10;q10) in ET.

Clinical Immunology, Bind 165, 2016, pp. 19-20

Cytokin, Bd. 96, 2017, S. 102-106

Cardiovascular diseases (CVD) are the leading cause of death in the industrialized world. Age is the most predictive risk factor for cardiovascular disease and is associated with arteritis, which contributes to an increased risk of cardiovascular disease. Although age-related arteritis has been described in both humans and animals, only a limited number of inflammatory mediators, cytokines and chemokines have been identified. In this study, we wanted to determine whether life-prolonging interventions, including waste overflow, early childhood nutrient deficiency (CL), traditional lifelong calorie restriction (CR), and lifelong treatment with rapamycin (Rap), would alleviate arterial inflammation. Age using multianalytic profiling. The aortae of young (4-6 months), old (22 months), old CL, old CR and old Rap mice were homogenized and cytokine levels were assessed using Luminex Multi Analyte Profiling. Chemokines involved in immune cell recruitment, such as CCL2, CXCL9, CXCL10, GMCSF, and MCSF, were increased in elderly and young subjects (p<0.05). CR prevented the age-related increase in CXCL10 (p<0.05 vs. old). MSCF levels were lower in the aorta of Rap-treated mice (p<0.05 compared to age). Interleukins (IL), IL-1α, IL-1β and IL-10 were also higher in old and young mice (p<0.05). These data show that selected life-prolonging interventions can prevent or limit age-related increases in selected aortic chemokines.

Lung Cancer, Vol. 89, Issue 2, 2015, pp. 110–114

The International Journal of Biochemistry & Cell Biology, Band 45, 9. Februar 2013, s. 1953-1961

Fanconi anemia (FA) proteins are known to play a role in the cellular response to changes in connectivity between DNA strands; However, several reports suggest that FA proteins play additional roles. To elucidate the novel functions of the FA proteins, we used a yeast two-hybrid screen to identify the binding partners for the Fanconi anemia-complementing group A protein (FANCA). The candidate proteins included kinase 2 (Nek2), which is associated with the never-mitotic gene A (NIMA) and whose role is to maintain centrosome integrity. The interaction between FANCA and Nek2 was confirmed in 293T human embryonic kidney (HEK) cells. Furthermore, FANCA interacted with γ-tubulin and localized to centrosomes, particularly during the mitotic phase, confirming that FANCA is a centrosomal protein. FANCA knockdown increased the frequency of centrosomal abnormalities and increased the sensitivity of U2OS osteosarcoma cells to nocodazole, a microtubule disrupting agent. In vitro kinase assays showed that Nek2 could phosphorylate FANCA at threonine-351 (T351), and analysis with a phosphorus-specific antibody confirmed that this phosphorylation occurs in response to nocodazole treatment. Furthermore, U2OS cells overexpressing the phosphorylation-defective T351A mutant FANCA displayed numerical centrosomal abnormalities, aberrant mitotic arrest, and increased nocodazole sensitivity, suggesting that Nek2-mediated phosphorylation of FANCA at the T351 centrosome is important for its maintenance of integrity is. In summary, this study revealed that FANCA localizes to centrosomes and is required for maintaining centrosome integrity, possibly through its phosphorylation at T351 by Nek2.

Blood Advances, Band 2, Ausgabe 6, 2018, S. 586–596

It has been reported that heterozygous mutations in MECOM (the site of the MDS1 and EVI1 complex) are the cause of a rare association between congenital amegakaryocytic thrombocytopenia and radioulnar synostosis. Here we describe 12 patients with congenital hypomegacaryocytic thrombocytopenia due to MECOM mutations (including 10 new mutations). The mutations affected different functional domains of the EVI1 protein. The spectrum of phenotypes was much broader than originally reported for the first three patients; We found both familial and sporadic cases, and the clinical spectrum ranged from isolated radioulnar synostosis with little or no hematologic involvement to severe bone marrow failure with no obvious skeletal abnormalities. The clinical presentations included radioulnar synostosis, bone marrow failure, clinodactyly, cardiac and renal malformations, B cell deficiency and presenile hearing loss. No single clinical manifestation was identified in all patients affected by MECOM mutations. Radioulnar synostosis and B cell deficiency were only observed in patients with mutations affecting a short region in the C-terminal domain of the EVI1 zinc finger. We propose the naming of this heterogeneous inherited disease MECOM-associated syndrome and the inclusion of MECOM sequencing in the diagnosis of congenital bone marrow failure.

Cancer Genetics, Bind 216-217, 2017, pp. 1-9

Recently, the occurrence of clonal chromosomal aberrations in Philadelphia-negative (CCA/Ph) cells during treatment of chronic myeloid leukemia (CML) has been confirmed. The meaning of these results is not clearly defined. We present data on time of onset, persistence, size of the CCA/Fh clone relative to drugs used, and percentage of hematological, cytogenetic, and molecular response. The focus was on peripheral blood cytopenias and myelodysplastic changes in the microscopic assessment of the bone marrow. Five of 155 (3.2%) CML patients had persistent (up to nine years) CCA/Ph− (monosomy 7 and trisomy 8 in unrelated clones in two tyrosine kinase inhibitor-treated patients; trisomy 8 in two imatinib-treated patients patients; trisomy 21). in a patient treated with alpha interferon). In 3-15 consecutive analyzes at different time points of the cytogenetic and molecular response, an average of 24% of Ph cells showed abnormalities. Patients with CCA/Ph− did not develop visible myelodysplastic changes or transformation to MDS/AML. All patients achieved a strong molecular response (MMR). It appears that the presence of CCA/Ph- does not affect the long-term outcomes of treatment in patients with chronic myeloid leukemia. Further comprehensive surveillance of CML patients with CCA/Ph- is still required.