Search Results (7)

Despite recent advances in immunophenotyping, the prognosis of acute myeloid leukemia (AML) is still mainly estimated using age and genetic markers. As the genetic heterogeneity of AML patients is high, flow cytometry-based classification with appropriate biomarkers can efficiently complement risk stratification and treatment selection. An increased expression of B7-H3 (CD276), an immune checkpoint protein, has been reported and associated with poor prognosis. However, the available data are limited and heterogeneous. Here, we used a novel, proprietary murine anti-B7-H3 8H8 antibody for the flow cytometric analysis of B7-H3 expression in AML blasts from 77 patients. Our antibody reliably detected substantial B7-H3 expression in 62.3% of AML patients. B7-H3 expression was higher in the monocytic French–American–British (FAB) M5 group and in intermediate and poor risk patients according to the European Leukemia Network. Using receiver operating characteristics (ROCs), we identified a specific fluorescence intensity cut-off of 4.45 to discriminate between B7-H3^high and B7-H3^low expression. High B7-H3 expression was associated with shorter overall survival (OS) and progression-free survival (PFS). In conclusion, we have developed a novel B7-H3 antibody that serves as a new tool for the detection of B7-H3 expression in AML and may help to facilitate risk stratification and treatment selection in AML patients. Full article

We review the importance of monocytic differentiation and differentiation induction in non-APL (acute promyelocytic leukemia) variants of acute myeloid leukemia (AML), a malignancy characterized by proliferation of immature myeloid cells. Even though the cellular differentiation block is a fundamental characteristic, the AML cells can show limited signs of differentiation. According to the French–American–British (FAB-M4/M5 subset) and the World Health Organization (WHO) 2016 classifications, monocytic differentiation is characterized by morphological signs and the expression of specific molecular markers involved in cellular communication and adhesion. Furthermore, monocytic FAB-M4/M5 patients are heterogeneous with regards to cytogenetic and molecular genetic abnormalities, and monocytic differentiation does not have any major prognostic impact for these patients when receiving conventional intensive cytotoxic therapy. In contrast, FAB-M4/M5 patients have decreased susceptibility to the Bcl-2 inhibitor venetoclax, and this seems to be due to common molecular characteristics involving mitochondrial regulation of the cellular metabolism and survival, including decreased dependency on Bcl-2 compared to other AML patients. Thus, the susceptibility to Bcl-2 inhibition does not only depend on general resistance/susceptibility mechanisms known from conventional AML therapy but also specific mechanisms involving the molecular target itself or the molecular context of the target. AML cell differentiation status is also associated with susceptibility to other targeted therapies (e.g., CDK2/4/6 and bromodomain inhibition), and differentiation induction seems to be a part of the antileukemic effect for several targeted anti-AML therapies. Differentiation-associated molecular mechanisms may thus become important in the future implementation of targeted therapies in human AML. Full article

Even though morphological signs of differentiation have a minimal impact on survival after intensive cytotoxic therapy for acute myeloid leukemia (AML), monocytic AML cell differentiation (i.e., classified as French/American/British (FAB) subtypes M4/M5) is associated with a different responsiveness both to Bcl-2 inhibition (decreased responsiveness) and possibly also bromodomain inhibition (increased responsiveness). FAB-M4/M5 patients are heterogeneous with regard to genetic abnormalities, even though monocytic differentiation is common for patients with Nucleophosmin 1 (NPM1) insertions/mutations; to further study the heterogeneity of FAB-M4/M5 patients we did a proteomic and phosphoproteomic comparison of FAB-M4/M5 patients with (n = 13) and without (n = 12) NPM1 mutations. The proteomic profile of NPM1-mutated FAB-M4/M5 patients was characterized by increased levels of proteins involved in the regulation of endocytosis/vesicle trafficking/organellar communication. In contrast, AML cells without NPM1 mutations were characterized by increased levels of several proteins involved in the regulation of cytoplasmic translation, including a large number of ribosomal proteins. The phosphoproteomic differences between the two groups were less extensive but reflected similar differences. To conclude, even though FAB classification/monocytic differentiation are associated with differences in responsiveness to new targeted therapies (e.g., Bcl-2 inhibition), our results shows that FAB-M4/M5 patients are heterogeneous with regard to important biological characteristics of the leukemic cells. Full article

AML is a highly aggressive and heterogeneous form of hematological cancer. Proteomics-based stratification of patients into more refined subgroups may contribute to a more precise characterization of the patient-derived AML cells. Here, we reanalyzed liquid chromatography-tandem mass spectrometry (LC-MS/MS) generated proteomic and phosphoproteomic data from 26 FAB-M4/M5 patients. The patients achieved complete hematological remission after induction therapy. Twelve of them later developed chemoresistant relapse (RELAPSE), and 14 patients were relapse-free (REL_FREE) long-term survivors. We considered not only the RELAPSE and REL_FREE characteristics but also integrated the French-American-British (FAB) classification, along with considering the presence of nucleophosmin 1 (NPM1) mutation and cytogenetically normal AML. We found a significant number of differentially enriched proteins (911) and phosphoproteins (257) between the various FAB subtypes in RELAPSE patients. Patients with the myeloblastic M1/M2 subtype showed higher levels of RNA processing-related routes and lower levels of signaling related to terms like translation and degranulation when compared with the M4/M5 subtype. Moreover, we found that a high abundance of proteins associated with mitochondrial translation and oxidative phosphorylation, particularly observed in the RELAPSE M4/M5 NPM1 mutated subgroup, distinguishes relapsing from non-relapsing AML patient cells with the FAB subtype M4/M5. Thus, the discovery of subtype-specific biomarkers through proteomic profiling may complement the existing classification system for AML and potentially aid in selecting personalized treatment strategies for individual patients. Full article

Acute myeloid leukemia (AML) is a type of leukemia known for its unfavorable prognoses, prompting research efforts to discover new therapeutic targets. One area of investigation involves examining extracellular factors, particularly CXC chemokines. While CXCL12 (SDF-1) and its receptor CXCR4 have been extensively studied, research on other CXC chemokine axes in AML is less developed. This study aims to bridge that gap by providing an overview of the significance of CXC chemokines other than CXCL12 (CXCR1, CXCR2, CXCR3, CXCR5, and CXCR6 ligands and CXCL14 and CXCL17) in AML’s oncogenic processes. We explore the roles of all CXC chemokines other than CXCL12, in particular CXCL1 (Gro-α), CXCL8 (IL-8), CXCL10 (IP-10), and CXCL11 (I-TAC) in AML tumor processes, including their impact on AML cell proliferation, bone marrow angiogenesis, interaction with non-leukemic cells like MSCs and osteoblasts, and their clinical relevance. We delve into how they influence prognosis, association with extramedullary AML, induction of chemoresistance, effects on bone marrow microvessel density, and their connection to French–American–British (FAB) classification and FLT3 gene mutations. Full article

Although the outcome has improved over the past decades, due to improved supportive care, a better understanding of risk factors, and intensified chemotherapy, pediatric acute myeloid leukemia remains a life-threatening disease, and overall survival (OS) remains near 70%. According to French-American-British (FAB) classification, AML is divided into eight subtypes (M0–M7), and each is characterized by a different pathogenesis and response to treatment. However, the curability of AML is due to the intensification of standard chemotherapy, more precise risk classification, improvements in supportive care, and the use of minimal residual disease to monitor response to therapy. The treatment of childhood AML continues to be based primarily on intensive, conventional chemotherapy. Therefore, it is essential to identify new, more precise molecules that are targeted to the specific abnormalities of each leukemia subtype. Here, we review abnormalities that are potential therapeutic targets for the treatment of AML in the pediatric population. Full article

p53 protein isoform expression has been found to correlate with prognosis and chemotherapy response in acute myeloid leukemia (AML). We aimed to investigate how p53 protein isoforms are modulated during epigenetic differentiation therapy in AML, and if p53 isoform expression could be a potential biomarker for predicting a response to this treatment. p53 full-length (FL), p53β and p53γ protein isoforms were analyzed by 1D and 2D gel immunoblots in AML cell lines, primary AML cells from untreated patients and AML cells from patients before and after treatment with valproic acid (VPA), all-trans retinoic acid (ATRA) and theophylline. Furthermore, global gene expression profiling analysis was performed on samples from the clinical protocol. Correlation analyses were performed between p53 protein isoform expression and in vitro VPA sensitivity and FAB (French–American–British) class in primary AML cells. The results show downregulation of p53β/γ and upregulation of p53FL in AML cell lines treated with VPA, and in some of the patients treated with differentiation therapy. p53FL positively correlated with in vitro VPA sensitivity and the FAB class of AML, while p53β/γ isoforms negatively correlated with the same. Our results indicate that p53 protein isoforms are modulated by and may predict sensitivity to differentiation therapy in AML. Full article