Single Cell Analyses Reveal a Non-Canonical EZH2 Activity As a Main Driver of Retinoic Acid Resistance in PLZF/Rara Leukemia

Resistance to treatment is due to the heterogeneity of the tumor which contains a subset of cancer cells that escape treatment and are responsible for the relapse. Acute Promyelocytic Leukemia (APL), the M3 subtype of AML, is a good model to illustrate these problematics. Indeed, APL driven by oncogenic fusion proteins such PML/RARA t(15;17) or PLZF/RARA t(11;17) behave differently to differentiation therapeutics. Both APLs differentiate in vivo upon Retinoic Acid (RA) treatment; however, while PML/RARA APL patients exhibit partial or complete remission, PLZF/RARA APL patients remain clinically resistant. In the present study we aim to decipher the transcriptional and epigenetic networks that is linked to t(11;17) APL resistance towards RA. We took advantage of the PLZF/RARA RA resistant murine APL model to catch relapse-initiating cell features and their vulnerabilities. By developing an integrative single-cell multi-omics analysis (scRNA-seq and scATAC-seq), we uncovered transcriptional and chromatin heterogeneity of the PLZF/RARA APL blasts. We highlighted a subset of cells insensitive to RA-induced differentiation with a strong DNA repair signature ("Rep" cluster) and exhibiting a fine tuned transcriptional network targeting the histone methyltransferase Ezh2. To validate the function of Ezh2 in APL physiology, we combined epigenomic studies with RA-treated and non-RA-treated bone marrow transplantation experiments. We revealed high Ezh2 activity that marks the relapse of RA-treated APL. However, targeting Ezh2 methyltransferase activity was not sufficient to achieve disease cure and, suggests an independent methyltransferase Ezh2 activity linked to RA resistance. These findings demonstrate the power of single-cell multi-omics integration to highlight path to sensitize therapy-resistant leukemia cells. In addition, our study uncovers a dual role of Ezh2 in APL and suggests that targeting non-canonical Ezh2 activity could be a new promising therapeutic approach for RA resistant APL. Disclosures Iwama: Nissan Chemical Corporation: Research Funding.

SIGNIFICANCE OF THE EXPRESSION OF CD123 AND THEIR CLINICAL IMPACT IN ACUTE MYELOID LEUKEMIA AMONG SUDANESE PATIENTS

Background: Acute myeloid leukemia (AML) is a heterogeneous clonal disorder characterized by immature myeloid cell proliferation and bone marrow failure. This study was prospective study conducted in Khartoum state during period from October 2018 until 2021 Objective: This study was aimed to determine the significance of the expression of CD123 in Sudanese Patients with Acute Myeloid Leukemia, and their clinical impact. Method: The study population was selected as 100 AML patients as study group. 2.5 ml of venous blood were collected and poured into ethylene di-amine tetra acidic acid (EDTA) for examination of peripheral Blood smears and complete blood count, aspirate and trephine biopsy of bone marrow were collected for smearing and staining and detected CD markers by using flow cytometry Results: The result showed that 57.6% of AML patients with positive CD123. The study was revealed insignificant difference in CD123 in correlated to age with p.value=0.509, and also insignificant difference in CD123 when correlated to gender male and female with p.value=0.705, and the result showed that CD123 expression was significant decreased in bone marrow sample compared to peripheral sample with p.value=0.019, also the finding showed that CD123 expression was strongest being in M3 subtype (56.8+36.8) with P-value (0.099). Conclusion: This study was concluded that 57.6% of AML patients were positive for CD123 and also reflect thatCD123 expression was strongest being in M3 subtype. Keyword: Acute Myeloid Leukemia, CD123 ,Sudan .

Assessment of By-Product from Botryosphaeria rhodina MAMB-05 as an Effective Biosorbent of Pb(II)

In this work, two types of biomass preparations (VMSM and M3) from the filamentous fungus Botryosphaeria rhodina MAMB-05, which were previously used in a process of production of β-glucan, were assessed as biosorbents of lead. The operating conditions, optimized through response surface methodology and experimental design, were shown to be pH 5.29 and a biosorbent dose of 0.23 g/L for the VMSM biomass type; and pH 5.06 and a dose of biosorbent of 0.60 g/L for the M3 biomass type, at a constant temperature of 27 °C. Fourier transform-infrared spectroscopy analyzed the presence of functional groups on the biomass surface. In addition to give an extra value to the by-product biomass, the VMSM-type from B. rhodina MAMB-05 showed an excellent lead biosorption capacity (qm) with a value of 403.4 mg/g for the Langmuir model, comparing favorably with literature results, while the M3 subtype biomass showed a value of 96.05 mg/g.

MicroRNAs as Potential Biomarkers in Acute Promyelocytic Leukaemia

Acute promyelocytic leukaemia (APL) is an M3 subtype of acute myeloid leukaemia (AML). This classification is based on the morphology of promyelocytic cell. The clinical characteristics of APL can be recognized by haemorrhagic episodes, a differentiation block at the promyelocytic stage, and sensitivity to the differentiation response to all-trans-retinoic acid (ATRA). Cytogenetically, APL is characterized by a balanced reciprocal translocation between chromosomes 15 and 17, which results in the production of PML/RARα fusion protein. Recent studies reported that microRNAs (miRNAs) have also been proposed to contribute to the pathogenesis of APL. miRNAs have been associated with the pathogenesis of cancer and their involvement as oncogenic and tumour suppressor activities have been identified. They are involved in various biological processes including the cell proliferation, differentiation, growth and development, metabolism, apoptosis, and haematopoiesis. The new discovery of miRNAs as possible therapeutic markers will provide new insight for the diagnosis and therapeutic entries for the treatment of APL. This review highlights the potential of miRNAs as biomarkers in APL.