Irena Marjanović

University of Belgrade

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Sonja Pavlović

University of Belgrade

Nataša Tos̆ić

University of Belgrade

Teodora Karan-Djurašević

University of Belgrade

Nada Suvajdžić

Univerzitetski Klinički Centar Srbije

Tatjana Kostić

University of Belgrade

Marijana Virijević

University of Belgrade

Darko Antić

University of Belgrade

Vojin Vuković

University of Belgrade

Dragana Janić

Oncology Institute of Vojvodina

Vladimir Gašić

University of Belgrade

Cooperative Institutions

University of Belgrade

Centar za Promociju Nauke

Univerzitetski Klinički Centar Srbije

Institute of Molecular Genetics and Genetic Engineering

Center for Health, Exercise and Sport Sciences

Institute of Public Health of Serbia

Institute of Molecular Genetics

University of Belgrade – Faculty of Medicine

Newcastle University

University Children's Hospital, Belgrade

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Pediatric acute myeloid leukemia: Insight into genetic landscape and novel targeted approaches

Biochemical Pharmacology (2023)

Nataša Tos̆ić Irena Marjanović Jelena Lazić

Targeted Therapy

10.1016/j.bcp.2023.115705

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Citations (6)

PB2037: NEW TERT VARIANT IN A FAMILY WITH APLASTIC ANEMIA

HemaSphere (2023)

Marijana Virijević Irena Marjanović Marina Andjelković Nada Suvajdžić Ljubomir Jaković

Topic: 11. Bone marrow failure syndromes incl. PNH - Biology & Translational Research Background:TERT gene, the most frequently mutated gene in patients with telomere biology disorders (telomeropathies), encode telomerase reverse transcriptase enzyme. Heterozygous variants in the TERT gene impair telomerase activity by haploinsufficiency and pathogenic variants are associated with bone marrow failure syndrome and acute myeloid leukemia predisposition. TERT variants show incomplete penetrance and can also be found in asymptomatic family members. Some patients with telomeropathies present with severe symptoms at early age, and in other diseases may appear later in life like aplastic anemia, pulmonary or hepatic fibrosis. Affected families may show anticipation that may result in more severe forms of the disease in succeeding generations. Due to the rarity of the disease and the small number of clinical trials, telomeropathies are often unrecognized and misdiagnosed. Aims: To report a novel variant in TERT gene in familial hematopoietic disorder. Methods: Next Generation Sequencing of DNA isolated from peripheral blood of a patient (older sister) with clinical diagnosis of aplastic anemia, using TruSight One MiSeq platform (Illumina®) and segregation sequencing analysis of patient’s mother and younger sister. Results: We analyzed all three family members presented with a similar clinical appearance and hematology findings (moderate megaloblastic pancytopenia). Mother was diagnosed at age 14, but reevaluated before delivery in 2001 as hypoplastic MDS and trisomy 8 in karyotype with marked thrombocytopenia, being stable for years. Two daughters, both diagnosed as familiar aplastic anemia with normal karyotype, without elements of Fanconi anemia, at age of 13 and 14 yrs, also with profound thrombocytopenia without severe bleeding episodes. Moreover, lung and liver fibrosis were excluded. We identified a novel missense heterozygous variant c.2605G>A p.(Asp869Asn) in TERT gene in all three family members. This variant results in replacement of aspartic amino acid on 869 position in TERT enzyme polypeptide chain by asparagine. According to ACMG classification, detected variant is characterized as likely pathogenic, class 2. This variant is very rare and was detected in gnomAD exomes and gnomAD genomes data bases. It is located in highly conserved protein region and is very likely to disrupt the function of the enzyme. Summary/Conclusion: As patients with telomeropathies often have a history of macrocytosis and mild to moderate thrombocytopenia, that can be wrongly diagnosed as immune-mediated thrombocytopenia, myelodysplastic syndrome or moderate aplastic anemia, our findings indicate that TERT rare variants pass under-recognized in these patients. Therefore, this report emphasizes the importance for routine deep genetics screening for TERT rare variants in patients with family history of cytopenia, different bone marrow failure syndromes and aplastic anemia, regardless the age or clinical presentation. This investigation is able to identify clinically inapparent telomere biology disorder and improve outcomes through forehand diagnosis setting, genetic counseling and the precise therapy considerations especially stem cell grafting. E-Mail Address: [email protected] Keywords: Aplastic anemia, Telomere, Familial

Aplastic anemia

Haploinsufficiency

Bone marrow failure

Dyskeratosis congenita

10.1097/01.hs9.0000974956.62401.c5

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PB1821: THE INFLUENCE OF BCL2, BAX, BAX/BCL2 RATIO AND MDR1 GENE EXPRESSION ON PROGNOSIS OF ADULT DE NOVO ACUTE MYELOID LEUKEMIA PATIENTS WITH NORMAL KARYOTYPE

HemaSphere (2023)

Zlatko Pravdić Nada Suvajdžić Sonja Pavlović Milena Mitrović Marijana Virijević

Topic: 3. Acute myeloid leukemia - Biology & Translational Research Background: Deregulation of the apoptotic process underlies the pathogenesis of many cancers, including leukemia, but is also important for the success rate of chemotherapy. Therefore, the gene expression profile of main apoptotic factors, such as anti-apoptotic BCL2 (B-cell lymphoma protein 2) and pro-apoptotic BAX (BCL2-associated X), as well as genes involved in the multi-drug resistance (MDR1), could have significant impact on the prognosis of acute myeloid leukemia (AML). Aims: The influence of BCL2, BAX, and MDR1 expression on prognosis in AML patients with normal karyotype (AML-NK). Methods: We analyzed the expression of BCL2, BAX, and MDR1 in bone-marrow samples collected at diagnosis from 51 adult patients (age 18-65 years), male/female (26/25) with de novo AML-NK using real-time polymerase chain reaction method (PCR), and examined their prognostic potential. Baseline detection of FLT3-ITD and NPM1 mutations were analyzed also by PCR. All patients received induction chemotherapy with daunorubicin and cytarabine (3 + 7) followed by three consolidation cycles of high/intermediate doses of cytarabine. Median gene expression values were as follows: BCL2 1.22 (range 0.13-8.97), BAX 0.92 (range 0.27-2.64), BAX/BCL2 ratio 0.62 (range: 0.11-7.77), MDR1 0.16 (range 0.00-13.74). Based on the median expression values, patients were divided into: higher than median (BCL2+, BAX+, BAX/BCL2high and MDR1+) and lower than median (BCL2-, BAX-, BAX/BCL2low and MDR1-) expression groups. Overall and disease-free survival (OS and DFS) were calculated, while patients undergoing hematopoietic stem cell transplantation were censored at the time of transplantation (15 patients). Standard statistical methods were performed. Results: Increased expression of BCL2 (BCL2+) was associated with chemoresistance (p=0.018), while patients with low BAX expression (BAX-) were more prone to relapse (p=0.034). Analysis of the combined effect of BCL2 and BAX expression showed that 87% of patients with BAX/BCL2low ratio were refractory to chemotherapy (p=0.024). High expression of MDR1 (MDR1+) was associated with BCL2+ status (p<0.001), and with absence of NPM1 and FLT3-ITD mutations (p=0.048 and p=0.010, respectively). None of the analyzed genes influenced OS and DFS. Summary/Conclusion: Our analysis of BCL2, BAX and MDR1 gene expression profiles is the first study focusing exclusively on AML-NK patients. Preliminary results showed that patients with high BCL2 expression are likely to be chemo resistant, and possibly may benefit from specific anti-BCL2 treatment. Further investigations conducted on a larger number of patients could elucidate actual prognostic significance of these genes in AML-NK patients. Keywords: AML, ABC transporter, BCL2, Bax

NPM1

Daunorubicin

Induction chemotherapy

10.1097/01.hs9.0000974132.47827.a9

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Expression of BCL11A in chronic lymphocytic leukaemia

International Journal of Laboratory Hematology (2022)

Nataša Tos̆ić Milena Ugrin Irena Marjanović Tatjana Kostić Vojin Vuković

The B-cell lymphoma/leukaemia 11A (BCL11A) gene encodes a Krüppel-like transcription factor involved in lymphocyte development during normal haematopoiesis. Aberrant expression of BCL11A has been observed in several haematological malignancies, including chronic lymphocytic leukaemia (CLL). However, its functions in the regulatory networks of malignant B lymphocytes are poorly understood, as are the relations to clinical course and outcome of B-cell malignancies, particularly CLL.The expression of BCL11A was analysed in peripheral blood mononuclear cells of 87 newly-diagnosed CLL patients by quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR), and association with clinical and molecular variables was assessed.BCL11A was significantly overexpressed in CLL samples compared to control samples (p < 0.001). BCL11A expression level exhibited no association with age, sex, leukocyte, lymphocyte and platelet counts, haemoglobin level, serum β2-microglobulin, CD38 status and cytogenetic abnormalities. On the other hand, high BCL11A expression was associated with low serum lactate dehydrogenase (p = 0.031), Binet A stage (p = 0.047) and mutated IGHV (p = 0.028). In addition, a positive correlation with BCL2/BAX mRNA ratio was observed (r = 0.36; p < 0.001). Regarding the association with the time to first treatment (TTFT), a trend towards longer median TTFT in BCL11A high- versus BCL11A low-expressing cases was detected (21 vs. 6 months; p = 0.164).The results of this study show that BCL11A is upregulated in CLL patients, and that high BCL11A expression at diagnosis may be associated with better prognosis. These data are consistent with the role of BCL11A expression in CLL biology, and imply its potential prognostic relevance.

IGHV@

Hematology

10.1111/ijlh.13969

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Citations (7)

PB1776: EXPRESSION OF BCL2, BAX AND MDR1 GENES AS PHARMACOTRANSCRIPTOMIC MARKERS OF PROGNOSIS IN DE NOVO PATIENTS OF ADULT ACUTE MYELOID LEUKEMIA WITH NORMAL KARYOTYPE

HemaSphere (2023)

Vladimir Gašić Zlatko Pravdić Nada Suvajdžić Irena Marjanović Teodora Karan-Djurašević

Topic: 3. Acute myeloid leukemia - Biology & Translational Research Background: Acute myeloid leukemia (AML) is a malignancy of hematopoetic tissue which occurs due to a halt in differentiation, loss of proliferation control and dysregulated apoptosis of myeloid progenitor cells. It is the most common acute leukemia in adults, accounting for 80% of all cases. Stratification of AML patients is based on their karyotype. However, the constant introduction of new molecular markers of prognosis of AML patients calls for a different approach. In many cancers, as well as AML, dysregulation of apoptosis constitutes the basis of pathogenesis and this phenomenon is important to consider when the success of chemotherapy is in question. Another important factor of chemotherapy success is the degree of drug efflux. These factors constitute tumor resistance. Pharmacotranscriptomic markers of tumor resistance could be important targets for specific therapy, which, when applied, could improve prognosis in AML. The anti-apoptotic gene BCL2 (B-cell lymphoma protein 2) and the pro-apoptotic BAX (BCL2-associated X) expression levels are markers of non-pump tumor resistance (genes associated with apoptosis), while a marker of tumor pump resistance (gene which codes a protein associated with drug efflux) is the expression level of MDR1 (multi-drug resistance gene 1). These tumor resistance markers could have a significant impact on AML prognosis. Aims: By analyzing the gene expression profiles of BCL2, BAX and MDR1 and using statistics to identify association with clinical indicators of prognosis in adult AML patients with normal karyotype (AML-NK), the significance of these genes as molecular targets can be further elucidated. Methods: Bone-marrow samples at diagnosis were collected from 51 adult patients with AML-NK, who were treated with the same 3 + 7 protocol, followed by three consolidation cycles. Expressions of BCL2, BAX and MDR1 were analyzed using the real-time polymerase chain reaction method. Clinical data and expression values were statistically evaluated for possible associations Results: The presence of chemoresistance was found to be associated with overexpression of BCL2 (BCL2+) (p=0.018), while underexpression of BAX in patients has shown a greater affinity towards relapse (p=0.034). Evaluating the expressions of BCL2 and BAX in a combined effect has shown that 87% of patients with BAX/BCL2low status were resistant to therapy (p=0.024). BCL2+ status was associated with high expression of MDR1 (p<0.001). Likewise, high expression of MDR1 was associated with the absence of NPM1 and FLT3-ITD mutations (p=0.048 and p=0.010, respectively). Summary/Conclusion: This is the first study that focused only on AML-NK patients, when it comes to analysis of BCL2, BAX and MDR1 gene expression profiles. The results of this preliminary study have shown that high BCL2 expression would likely lead to tumor resistance from chemotherapy, making anti-BCL2 treatment a viable option in patients with this expression profile. A study on a larger group of patients could clarify the prognostic importance of the studied pharmacotranscriptomics markers, contributing to a creation of personalized treatment of adult AML-NK patients. Keywords: MDR1, Acute myeloid leukemia, Bax, BCL2

10.1097/01.hs9.0000973960.76802.0b

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Prognostic significance of combined BAALC and MN1 gene expression level in acute myeloid leukemia with normal karyotype

International Journal of Laboratory Hematology (2020)

Irena Marjanović Teodora Karan-Djurašević Tatjana Kostić Marijana Virijević Nada Suvajdžić

Abstract Introduction Acute myeloid leukemia with normal karyotype (AML‐NK) is the largest group of AML patients with very heterogeneous disease outcome. In order to ensure more precise risk stratification new molecular markers have been introduced, like expression level for BAALC (Brain and Acute Leukemia, Cytoplasmic) and MN1 (Meningioma 1) genes. Methods In this study, we investigated expression level of both genes in 111 adult AML‐NK at diagnosis and examined their prognostic potential. Results BAALC and MN1 expression were detected in about one third of the patients, and positive correlation between these two genes was found. The BAALC + /or MN1 + status was not associated with the presence of FLT3‐ITD mutations, but exhibited strong correlation with NPM1 wt status ( P < .001). Therefore, among BAALC + /or MN1 + patients the most frequent ones were FLT3‐ITD ‐ /NPM1 ‐ double negative patients with intermediate prognosis. When BAALC + /or MN1 + patients were divided into BAALC high /BAALC low (21/21) and MN1 high /MN1 low (21/22) groups, we detected that BAALC high /or MN1 high patients had a tendency toward lower complete remission rate. Also, survival analysis showed that BAALC high /or MN1 high patients had shorter disease‐free survival and overall survival (OS). The most pronounced influence on prognosis was detected in FLT3‐ITD ‐ /NPM1 ‐ group of patients that are lacking reliable prognostic markers, where OS in BAALC high /or MN1 high was only 5 months vs 25 months in BAALC low /or MN1 low . Conclusion These findings indicate that BAALC and MN1 expression level could be used for more precise risk stratification of AML‐NK patients and especially FLT3‐ITD ‐ /NPM1 ‐ patients, transforming this intermediate‐risk group, into a group with an adverse prognosis.

NPM1

10.1111/ijlh.13405

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Citations (3)

Gene Mutation Profiles in Primary Diffuse Large B Cell Lymphoma of Central Nervous System: Next Generation Sequencing Analyses

International Journal of Molecular Sciences (2016)

Milena Todorović Jelena Jelicic Biljana Mihaljević Jelena Kostic Bojana Stanić

The existence of a potential primary central nervous system lymphoma-specific genomic signature that differs from the systemic form of diffuse large B cell lymphoma (DLBCL) has been suggested, but is still controversial. We investigated 19 patients with primary DLBCL of central nervous system (DLBCL CNS) using the TruSeq Amplicon Cancer Panel (TSACP) for 48 cancer-related genes. Next generation sequencing (NGS) analyses have revealed that over 80% of potentially protein-changing mutations were located in eight genes (CTNNB1, PIK3CA, PTEN, ATM, KRAS, PTPN11, TP53 and JAK3), pointing to the potential role of these genes in lymphomagenesis. TP53 was the only gene harboring mutations in all 19 patients. In addition, the presence of mutated TP53 and ATM genes correlated with a higher total number of mutations in other analyzed genes. Furthermore, the presence of mutated ATM correlated with poorer event-free survival (EFS) (p = 0.036). The presence of the mutated SMO gene correlated with earlier disease relapse (p = 0.023), inferior event-free survival (p = 0.011) and overall survival (OS) (p = 0.017), while mutations in the PTEN gene were associated with inferior OS (p = 0.048). Our findings suggest that the TP53 and ATM genes could be involved in the molecular pathophysiology of primary DLBCL CNS, whereas mutations in the PTEN and SMO genes could affect survival regardless of the initial treatment approach.

10.3390/ijms17050683

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Citations (34)

Novel telomerase reverse transcriptase gene mutation in a family with aplastic anaemia

Familial Cancer (2024)

Marijana Virijević Irena Marjanović Marija Andjelkovic Lj Jakovic Dušan Micić

Human genetics

10.1007/s10689-024-00399-8

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Expression Pattern and Prognostic Significance of EVI1 Gene in Adult Acute Myeloid Leukemia Patients with Normal Karyotype

Indian Journal of Hematology and Blood Transfusion (2019)

Irena Marjanović Teodora Karan-Djurašević Tatjana Kostić Marijana Virijević Nada Suvajdžić

NPM1

Hematology

Clinical Significance

10.1007/s12288-019-01227-1

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Citations (7)

Germline Variants in Cancer Predisposition Genes in Pediatric Patients with Central Nervous System Tumors

International Journal of Molecular Sciences (2023)

Aleksa Jovanović Nataša Tos̆ić Irena Marjanović Jovana Komazec Branka Zukić

Central nervous system (CNS) tumors comprise around 20% of childhood malignancies. Germline variants in cancer predisposition genes (CPGs) are found in approximately 10% of pediatric patients with CNS tumors. This study aimed to characterize variants in CPGs in pediatric patients with CNS tumors and correlate these findings with clinically relevant data. Genomic DNA was isolated from the peripheral blood of 51 pediatric patients and further analyzed by the next-generation sequencing approach. Bioinformatic analysis was done using an "in-house" gene list panel, which included 144 genes related to pediatric brain tumors, and the gene list panel Neoplasm (HP:0002664). Our study found that 27% of pediatric patients with CNS tumors have a germline variant in some of the known CPGs, like ALK, APC, CHEK2, ELP1, MLH1, MSH2, NF1, NF2 and TP53. This study represents the first comprehensive evaluation of germline variants in pediatric patients with CNS tumors in the Western Balkans region. Our results indicate the necessity of genomic research to reveal the genetic basis of pediatric CNS tumors, as well as to define targets for the application and development of innovative therapeutics that form the basis of the upcoming era of personalized medicine.

MLH1

Pediatric cancer

CHEK2

MSH2

MSH6

Personalized Medicine

10.3390/ijms242417387

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Citations (2)