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Tyrosine kinase inhibitor (TKI) therapy is the current treatment of choice for patients with chronic phase chronic myeloid leukemia (CML) leading to rapid and durable hematological as well as molecular responses. However, emergence of resistance to TKIs has been the major obstacle to treatment success on long term. In this regard kinase domain mutations are the most common mechanism of therapy failure. In this study, we analyzed peripheral blood samples from 17 CML patients who had developed resistance to various TKIs by using next-generation sequencing parallel to Sanger sequencing. BCR-ABL1 kinase domain mutations have been found in 59% of the cohort. Our results demonstrate that next-generation sequencing results in a higher mutational detection rate than reported with conventional sequencing methodology. Furthermore, it showed the clonal diversity more accurately. [ABSTRACT FROM AUTHOR]

Objectives: Newer tyrosine kinase inhibitors (TKIs) (bosutinib, ponatinib) and allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be utilized as a salvage therapy in patients with chronic myeloid leukemia (CML) who failed two lines (imatinib → nilotinib or imatinib → dasatinib) of TKI therapy. However, these TKIs are not available in many countries and not all patients can undergo allo-HSCT. Methods: In this study, CML patients who received dasatinib or nilotinib as a third-line treatment were retrospectively evaluated. Results: Out of 209 patients, third-line dasatinib/nilotinib was administered in 21. During the follow-up, 16 out of 21 patients gained and/or maintained an optimal response, and 4 patients died due to progression. Seventeen patients were alive at the time of the analysis, of which 13 were still on TKI, whereas 4 patients quit treatment. Discussion: In patients failing two lines of TKI, dasatinib or nilotinib can be beneficial and safely administered as a third-line treatment especially in nations with restricted resources. [ABSTRACT FROM AUTHOR]

There is preliminary evidence that the local renin-angiotensin system (RAS) could affect neoplastic hematopoiesis. The aim of this study is to search messenger RNA (mRNA) expressions of the essential RAS elements in myeloid and lymphoid hematological neoplastic disorders. Forty-six patients with newly diagnosed myeloid (AML, biphenotypic leukemia, CML) or lymphoid (CLL, NHL, B-ALL, T-ALL) hematological disorders were included in the study. In the lymphoid group, the median expression values of RENIN, ACE1, ACE2 and ANGIOTENSINOGEN (ANGTS) mRNAs were 1.96%, 0.42%, 0.00% and 0.00%, respectively; in the myeloid group, 0.73%, 1.55%, 0.04% and 0.006%, respectively. In the lymphoid group, RENIN levels were significantly higher (p = 0.001), whereas ACE1 and ACE2 levels were significantly higher in the myeloid group (p values were 0.013 and 0.010, respectively). ANGTS levels were similar in both groups. In patients with non-ALL lymphoid malignancies, RENIN expressions were significantly higher when compared to ALL patients (p = 0.004). All patients with active disease had significantly higher RENIN mRNA expression levels than patients without active disease (2.03% vs 0.30%) (p = 0.034). The result of our present study indicates that the activities of local RAS may differ in distinct disease states such as leukemia and lymphomas. [ABSTRACT FROM PUBLISHER]

The NOTCH signaling pathway plays important role in the development of multicellular organisms, as it regulates cell proliferation, survival, and differentiation. In adults, it is essential for the T- or B-lymphocyte lineage commitment. NOTCH1 and FBXW7 mutations both lead the activation of the NOTCH1 pathway and are found in the majority of T-ALL patients. In this study, the mutation analysis of NOTCH1 and FBXW7 genes was performed in 87 pediatric T-ALLs who were treated on the ALL-BFM protocols. In 19 patients (22%), activating NOTCH1 mutations were observed either in the heterodimerization domain or in the PEST domain and 7 cases (10%) demonstrated FBXW7 mutations (2 cases had both NOTCH1 and FBXW7 mutations). We also analyzed the relationship of the mutation data between the clinical and biological data of the patients. NOTCH1 and FBXW7, NOTCH1 alone were found correlated with lower initial leucocyte counts which was independent from the sex and T- cell immunophenotype. However, NOTCH1 and FBXW7 mutations were not predictive of outcome in the overall cohort of pediatric T-ALLs. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented on genetic modifications in Wnt pathway members observed during acute leukemia.

Wingless Type (WNT) signaling pathway is an evolutionarily conserved pathway that is crucial for the cell fate determination, survival and expansion of lymphocyte progenitors. It has been demonstrated that deregulated WNT signaling is one of the participating mechanism underlying lymphoid leukemogenesis. Inactivating mutations and methylation in Adenomatous Polyposis Coli (APC) gene, a negative regulator of WNT pathway, can cause ligand independent WNT pathway simulation. In this study, promoter methylation and expression of the APC gene is evaluated in childhood lymphoid and myeloid acute leukemia patients (n= 118) and representative cell lines by using methylation specific PCR (MS-PCR) and real time quantitative PCR (QRT-PCR). APC gene promoter found hypermethylated in the 56% of childhood acute leukemia patients [49.2% of B-cell acute lymphoblastic leukemia (B-ALL), 62.5% of T-cell acute lymphoblastic leukemia (T-ALL) and 64.1% of Acute myeloid leukemia (AML)]. To evaluate the reflection of promoter methylation, APC mRNA levels were examined and found that all acute lymphoblastic leukemia subgroups have statistically lower APC expression levels compared to controls. Although there was no association with clinical parameters, promoter hypermethylation of APC gene seems to be a common epigenetic event in acute leukemia and leading to differential expression levels among different acute leukemia phenotypes. [ABSTRACT FROM AUTHOR]

Fms-like tyrosine kinase 3 (FLT3) and Nucleophosmin1 (NPM1) mutations are the most common molecular variations in acute myeloid leukemia (AML) and have been associated with prognosis. The frequencies of FLT3, NPM1 mutations in the Algeria population remains unknown due to the lack of data related to this subject. Herein, we aim to investigate the prevalence of these mutations in our population and assess their prognosis impact. Adult AML patients (n= 60) were analyzed for FLT3-internal tandem duplication (ITD), D835Y point mutation and NPM1 exon12 mutations. FLT3-ITD was detected using polymerase chain reaction (PCR), D835Y mutation was detected by restriction fragment length polymorphism (PCR-RFLP) and NPM1 exon12 was detected by Sanger sequencing. The relation between the mutations and the clinical features of the patients was evaluated. FLT3 mutations were present in 11.6% and NPM1 mutations were observed in 15.09% of AML patients. The most frequent NPM1 mutation type was the "type-A mutation" (87.5%). Furthermore, a novel "indel" mutation was also detected in one patient. According to the statistical analysis results, FLT3mut group showed shorter survival time and poor response to the induction therapy, while NPM1 was a predictor of better prognosis in the absence of FLT3 mutations. Our results reveal that FLT3 and NPM1 mutations are less frequent in our population than reported in literature. Patients with isolated NPM1 and FLT3 mutation have different clinical features than those with combined mutations. NPM1 and FLT3 mutations can be used as prognostic factors in AML risk classification. [ABSTRACT FROM AUTHOR]

The aim of this study is to search critical renin-angiotensin system (RAS) elements in myeloid leukemic cell lines. Human acute myeloid leukemia (AML) cell lines, KG-1 and HL-60, were cultured. We searched for the gene expression of the major RAS components in KG-1 and HL-60 cell lines by quantitative real-time polymerase chain reaction analysis (qRT-PCR). Angiotensin-converting enzyme I (ACE I) and ACE II mRNA expressions were detected in KG-1 AML cell line. Relative expression of ACE I was higher than ACE II expression in this myeloid leukemic cells. Likewise, RENIN, angiotensinogen (ANGTS), and ACE I mRNA expressions were detected in HL-60 promyelocytic cell line. Relative RENIN expression was the highest, whereas ACE I expression was the lowest in HL- 60 neoplastic myeloid cells. These findings indicate that there is a biologically active local RAS in the hematopoietic system in normal and pathological states. [ABSTRACT FROM AUTHOR]

Hodgkin's lymphoma (HL) is the most common cancer in adolescents and young adults. A family history of HL increases the risk of developing HL in other family members. Identification of genetic predisposition variants in HL is important for understanding disease aetiology, prognosis, and response to treatment. Aberrant activation of the NF-κB pathway is a hallmark feature of HL, contributing to the survival and proliferation of the malignant cells' characteristic of HL. The family with multiple consanguineous marriages with siblings of diagnosed HL was examined by whole-exome sequencing. We found a germline homozygous variation in the PXR ligand binding domain (NM&#95;003889.3: c.811G>A, p.(Asp271Asn)), which was classified as pathogenic by prediction tools and segregated in HL cases. Increased PXR expression was found in homozygous variant carriers compared to heterozygous carriers by quantitative real time PCR (qRT-pCR) and immunofluorescence staining of patients' formalin-fixed paraffin-embedded tissues showed upregulation of PXR, particularly in Hodgkin Reed/Sternberg (HRS) cells. Patients with homozygous PXR variant showed significantly high expression compared to PXR wild-type HL, heterozygous and controls (p=0.0001, p=0.0004 and p=0.0001, respectively). PXR homozygous HRS cells had significantly higher PXR expression compared to PXR wild-type HRS cells (p < 0.0001, 3.27-fold change). Albeit PXR's prominent expression in cytoplasm of HRS cells, homozygous PXR HRS cells showed increased PXR expression in nucleus (p < 0.001). PXR is a member of the nuclear receptor superfamily and previous studies have demonstrated a pleiotropic effect of PXR on malignant transformation. Expression analysis showed that cell proliferation, apoptosis and inflammation related genes were deregulated, in homozygous PXR HL cases. This study provided clinical evidence to previously reported Sxr -/- mice model that develop multifocal lymphomas, had an aberrantly increased NF-κB expression and consistent inflammation. Further functional studies are needed to elucidate the exact mechanisms of action of PXR in HL pathogenesis., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2024. Published by Elsevier Masson SAS.)