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Introduction: The introduction of CAR-T cell treatment for relapsed/refractory (r/r) mantle cell lymphoma improved survival rates of these patients. Along with its introduction in clinical routine, long-term events after CAR-T cell treatment are increasingly emerging. Case Presentation: We report the case of a patient developing acute erythroid leukemia with biallelic TP53 inactivation occurring 26 months after CAR-T therapy with brexucabtagene autoleucel (brexu-cel) for r/r mantle cell lymphoma. The patient presented with a healthy bone marrow prior to lymphoma treatments. Discussion: Secondary malignancies seem more frequent after CAR-T therapies. More studies are needed to assess potential long-term toxicities of CAR-T cell therapies including the frequency of secondary myeloid malignancies. [ABSTRACT FROM AUTHOR]

Pure erythroid leukemia (PEL) is an extremely rare subtype of acute myeloid leukemia (AML). Although not specific, PEL is almost uniformly associated with complex karyotype and TP53 mutations. Given the rarity of the disease, our understanding of its cytogenetic and molecular features deems incomplete. We aim to complement existing literature by presenting an unusual case of PEL. The case is comprehensively worked up with multiple modalities. We present for the first time a case of PEL with unusual cytogenetic and molecular features: normal karyotype with absence of TP53 mutations and presence of NPM1 and NRAS mutations. This is a valuable addition to literature, expanding our understanding of molecular and cytogenetic spectra of PEL. [ABSTRACT FROM AUTHOR]

Introduction: The introduction of CAR-T cell treatment for relapsed/refractory (r/r) mantle cell lymphoma improved survival rates of these patients. Along with its introduction in clinical routine, long-term events after CAR-T cell treatment are increasingly emerging. Case Presentation: We report the case of a patient developing acute erythroid leukemia with biallelic TP53 inactivation occurring 26 months after CAR-T therapy with brexucabtagene autoleucel (brexu-cel) for r/r mantle cell lymphoma. The patient presented with a healthy bone marrow prior to lymphoma treatments. Discussion: Secondary malignancies seem more frequent after CAR-T therapies. More studies are needed to assess potential long-term toxicities of CAR-T cell therapies including the frequency of secondary myeloid malignancies.

Simple Summary: Dendritic cells are important mediators in the activation of the innate and adoptive immune response. The generation of DC/DCleu was comparable under physiological hypoxic and normoxic culture conditions, with no significant differences in frequencies of generated DC/DCleu from leukemic cell lines, peripheral blood mononuclear as well as whole blood cells from patients with acute myeloid leukemia. Moreover, the composition of immune cells and anti-leukemic immune activity after T cell enriched mixed lymphocyte culture with patients' blood pretreated vs not pretreated with defined response modifiers (Kits) was improved, particularly under hypoxic conditions. These data show that the generation of DC/DCleu as well as the induction of anti-leukemic immune activating functionality is possible under standard normoxic as well as physiological hypoxic culture conditions ex vivo. Hypoxia can modulate the immune system by affecting the function and activity of immune cells, potentially leading to altered immune responses. This study investigated the generation of leukemia-derived dendritic cells (DCleu) from leukemic blasts and their impact on immune cell activation under hypoxic (5–10% O2) compared to normoxic (21% O2) conditions using various immunomodulatory Kits. The results revealed that DC/DCleu-generation was similar under hypoxic and normoxic conditions, with no significant differences observed in frequencies of generated DC/DCleu. Furthermore, the study showed that the activation of immune cells and their anti-leukemic activity improved when T cell-enriched immunoreactive cells were co-cultured with DC/DCleu which were generated with Kit I and M compared to the control after mixed lymphocyte cultures. The anti-leukemic activity was improved under hypoxic compared to normoxic conditions after MLCWB-DC Kit M. These findings suggest that DC/DCleu-cultures of leukemic whole blood with Kits under hypoxic conditions yield comparable frequencies of DC/DCleu and can even increase the anti-leukemic activity compared to normoxic conditions. Overall, this research highlights the potential of utilizing DC/DCleu (potentially induced in vivo with Kits) as a promising approach to enhance immune response in patients with acute myeloid leukemia. [ABSTRACT FROM AUTHOR]

Acute Erythroid Leukemia (AEL) is a rare and aggressive subtype of Acute Myeloid Leukemia (AML). In 2022, the World Health Organization (WHO) defined AEL as a biopsy with ≥30% proerythroblasts and erythroid precursors that account for ≥80% of cellularity. The International Consensus Classification refers to this neoplasm as "AML with mutated TP53". Classification entails ≥20% blasts in blood or bone marrow biopsy and a somatic TP53 mutation (VAF > 10%). This type of leukemia is typically associated with biallelic TP53 mutations and a complex karyotype, specifically 5q and 7q deletions. Transgenic mouse models have implicated several molecules in the pathogenesis of AEL, including transcriptional master regulator GATA1 (involved in erythroid differentiation), master oncogenes, and CDX4. Recent studies have also characterized AEL by epigenetic regulator mutations and transcriptome subgroups. AEL patients have overall poor clinical outcomes, mostly related to their poor response to the standard therapies, which include hypomethylating agents and intensive chemotherapy. Allogeneic bone marrow transplantation (AlloBMT) is the only potentially curative approach but requires deep remission, which is very challenging for these patients. Age, AlloBMT, and a history of antecedent myeloid neoplasms further affect the outcomes of these patients. In this review, we will summarize the diagnostic criteria of AEL, review the current insights into the biology of AEL, and describe the treatment options and outcomes of patients with this disease. [ABSTRACT FROM AUTHOR]

Simple Summary: Allogeneic stem cell transplantation (aHSCT) is the only potentially curative treatment option for patients with high-risk myeloid malignancies. Depending on the underlying genetic risk profile, up to 50% of patients die of relapse even after aHSCT in first remission. Therefore, further improvement of conditioning regimens is an urgent medical need. Current sequential conditioning regimens combine intensive AML-like induction therapy with total body irradiation or alkylators like treosulfan or melphalan. The first and currently widely accepted prototype of this treatment strategy is the fludarabine/amsacrine/ara-C (FLAMSA) protocol, which has been modified multiple times by changing parts or adding additional cytotoxic drugs to improve clinical results. Knowing that venetoclax, an inhibitor of B-cell lymphoma-2 protein (BCL2), has synergistic effects to chemotherapy without increasing the level of non-hematologic toxicity, several German transplant centers have added venetoclax to the FLAMSA protocol as an individualized treatment approach to improve long term outcome in patients with high-risk myeloid malignancies. Up to 50% of patients with high-risk myeloid malignancies die of relapse after allogeneic stem cell transplantation. Current sequential conditioning regimens like the FLAMSA protocol combine intensive induction therapy with TBI or alkylators. Venetoclax has synergistic effects to chemotherapy. In a retrospective survey among German transplant centers, we identified 61 patients with myeloid malignancies that had received FLAMSA-based sequential conditioning with venetoclax between 2018 and 2022 as an individualized treatment approach. Sixty patients (98%) had active disease at transplant and 74% had genetic high-risk features. Patients received allografts from matched unrelated, matched related, or mismatched donors. Tumor lysis syndrome occurred in two patients but no significant non-hematologic toxicity related to venetoclax was observed. On day +30, 55 patients (90%) were in complete remission. Acute GvHD II°–IV° occurred in 17 (28%) and moderate/severe chronic GvHD in 7 patients (12%). Event-free survival and overall survival were 64% and 80% at 1 year as well as 57% and 75% at 2 years, respectively. The off-label combination of sequential FLAMSA-RIC with venetoclax appears to be safe and highly effective. To further validate these insights and enhance the idea of smart conditioning, a controlled prospective clinical trial was initiated in July 2023. [ABSTRACT FROM AUTHOR]

Acute Erythroid Leukemia (AEL) is a rare and aggressive subtype of Acute Myeloid Leukemia (AML). In 2022, the World Health Organization (WHO) defined AEL as a biopsy with ≥30% proerythroblasts and erythroid precursors that account for ≥80% of cellularity. The International Consensus Classification refers to this neoplasm as “AML with mutated TP53”. Classification entails ≥20% blasts in blood or bone marrow biopsy and a somatic TP53 mutation (VAF > 10%). This type of leukemia is typically associated with biallelic TP53 mutations and a complex karyotype, specifically 5q and 7q deletions. Transgenic mouse models have implicated several molecules in the pathogenesis of AEL, including transcriptional master regulator GATA1 (involved in erythroid differentiation), master oncogenes, and CDX4. Recent studies have also characterized AEL by epigenetic regulator mutations and transcriptome subgroups. AEL patients have overall poor clinical outcomes, mostly related to their poor response to the standard therapies, which include hypomethylating agents and intensive chemotherapy. Allogeneic bone marrow transplantation (AlloBMT) is the only potentially curative approach but requires deep remission, which is very challenging for these patients. Age, AlloBMT, and a history of antecedent myeloid neoplasms further affect the outcomes of these patients. In this review, we will summarize the diagnostic criteria of AEL, review the current insights into the biology of AEL, and describe the treatment options and outcomes of patients with this disease.

The article presents a case study of a 46-year-old man with relapsed acute myeloid leukemia who underwent a second stem cell transplant from a matched related donor.It mentions that after the transplant, the patient developed various symptoms, including fever, sinusitis, eye issues, skin nodules, leukopenia, anemia, and thrombocytopenia.

Abstract Acute erythroid leukemia (AEL) is a rare (2%–5%) form of acute myeloid leukemia (AML). Molecular alterations found in AEL resemble those of other AMLs. We report a classification of AELs in three major classes, with different prognosis and some specific features such as a tendency to mutual exclusion of mutations in epigenetic regulators and signaling genes.

Simple Summary: Recent breakthroughs in cancer therapeutics have occurred through the recognition of the immune system's role in cancer cell eradication and surveillance. While these breakthroughs have primarily occurred in solid tumors, the role of immunotherapy as an anti-cancer treatment is best described through decades of work in allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute leukemias. Herein we review the history and mechanisms behind allo-HSCT and discuss how lessons learned through transplants and cancer evasion of the host immune system can be applied toward acute leukemias to provide future therapies. Immunotherapy as a cancer treatment modality has undergone recent widespread proliferation across all cancer types, especially amongst patients with solid tumors. However, the longest tenured immunotherapy approach to cancer is allogeneic stem cell transplantation (allo-SCT) for two hematologic malignancies: acute myeloid and acute lymphoid leukemia (AML and ALL, respectively). While allo-SCT remains a standard of care for eligible patients, recent advances/applications of monoclonal antibodies, immune checkpoint inhibitors, bispecific T-cell engagers (BiTEs), and CAR T-cell therapy are changing the treatment landscape for these acute leukemias by either direct to tumor immune targeting or through decreased toxicities that expand patient eligibility. Pre-clinical data and clinical trials have shown promising results for novel immunotherapies in acute leukemia, and multiple ongoing trials are investigating these novel approaches. While there have been promising results with these approaches, particularly in the relapsed/refractory setting, there remain challenges in optimizing the use of these therapies, such as managing cytokine release syndrome and other immune-related toxicities. Immunotherapy is a rapidly evolving field in the treatment of acute leukemia and has the potential to significantly impact the management of both AML and ALL. This review highlights the history of immunotherapy in the treatment of acute leukemias, the evolution of immunotherapy into more targeted approaches, the potential benefits and limitations of different immune targeting approaches, and ongoing research and development in the field. [ABSTRACT FROM AUTHOR]

Acute erythroid leukemia (AEL) is a disease continuum between Myelodysplastic syndrome (MDS) and Acute myeloid leukemia (AML) with the cellular hallmark of uncontrolled proliferation and impaired differentiation of erythroid progenitor cells. First described by Giovanni di Guglielmo in 1917 AEL accounts for less than 5% of all de novo AML cases. There have been efforts to characterize AEL at a molecular level, describing recurrent alterations in TP53, NPM1 and FLT3 genes. A genomic analysis of AEL cases confirmed its complexity. Despite these advances, the biology underlying erythroid proliferations remains unclear and the prognosis is dismal with a median survival of only 3 months for pure erythroid leukemia (PEL). Marker combinations suitable for the identification and characterization of leukemic stem cell (LSC) candidates, monitoring measurable residual disease (MRD) during chemotherapy treatment and the development of innovative targeted therapies are missing. Here, we developed a mass cytometry panel for an in‐depth characterization of erythroid and myeloid blast cell populations from human AEL bone marrow samples in comparison to other AML subtypes and healthy counterparts. A total of 8 AEL samples were analyzed and compared to 28 AML samples from different molecular subtypes, healthy bone marrow counterparts (n = 5) and umbilical cord blood (n = 6) using high‐dimensional mass cytometry. Identification of erythroid and myeloid blast populations in high‐dimensional mass cytometry data enabled a refined view on erythroblast differentiation stages present in AEL erythroid blasts and revealed immunophenotypical profiles specific to AEL. Profiling of phenotypic LSCs revealed aberrant erythroid marker expression in the CD34+CD38− stem cell compartment. In addition, the identification of novel candidate surface marker combinations and aberrancies might enhance clinical diagnostics of AEL. We present a high‐parameter mass cytometry approach feasible for immunophenotypical analysis of blast and stem cell populations in myeloid neoplasms with erythroid predominance laying the foundation for more precise experimental approaches in the future. [ABSTRACT FROM AUTHOR]

This article describes the laboratory diagnostics stages of acute erythroid leukemia clinical case. The following research results allow observing the process of disease formation in development.

Chronic myeloid leukemia (CML), a myeloproliferative neoplasm defined by the presence of the BCR-ABL1 oncogene created by the reciprocal translocation t(9;22)(q34.1;q11.2), can often be controlled by medications that inhibit this constitutive tyrosine kinase. However, if these therapies fail, the disease may progress to a form resembling an acute leukemia. While most of these CML 'blast crises' are characterized by blasts with a myeloid (granulocytic) or lymphoid lineage, these blasts may rarely be predominantly erythroid. Cases of CML erythroid blast crises have been reported; however, secondary pure erythroid leukemia arising from a CML blast crisis has only been definitively reported once before. We report the second definitive case of pure erythroid leukemia with the t(9;22)(q34.1;q11.2) presenting as a CML blast crisis and characterize the morphologic, immunophenotypic, flow cytometric, cytogenetic, and molecular findings. [ABSTRACT FROM AUTHOR]

Factor VII (FVII) deficiency is the most common among all rare inherited bleeding disorders. However, acquired FVII deficiency (aFVIID) is uncommon. Only few cases in the literature have been reported. Herein, we present a case of an aFVIID associated with acute myeloid leukemia (AML), along with a literature review regarding this condition. A 50 year old Arab male patient was diagnosed with AML at the hematology department of our institution. At admission, coagulation tests showed a prolonged prothrombin time (PT) with a normal activated partial thromboplastin time (aPTT) and a slightly elevated fibrinogen level. Prothrombin complex coagulation factors dosing (PCCFD) revealed a decrease only in FVII levels. The patient, however, did not experience any bleeding. The evolution of the health of the patient was marked by a normalization of PT and FVII levels and complete remission. [ABSTRACT FROM AUTHOR]

Objectives: Pure erythroid leukemia (PEL) is exceptionally rare in the pediatric setting. Four pediatric PEL cases with t(1;16)(p31;q24) NFIA-CBFA2T3 were reported previously. We present a case of an infant with PEL presenting with erythroblastic sarcoma and harboring a novel t(1;8)(p31.3;q21.3) NFIA-RUNX1T1 fusion detected by RNA sequencing and conventional karyotype.Methods: Bone marrow (BM) and abdominal mass biopsies from the patient were evaluated with extensive immunohistochemical, flow cytometric, cytogenetic, and molecular studies.Results: The patient was a female infant who presented between 2 and 5 months of age with cytopenias and an enlarging abdominal mass. Blasts in the BM and abdominal mass expressed CD71 and CD117 with focal expression of CD43, E-cadherin, epithelial membrane antigen, and hemoglobin A. They were negative for additional myeloid, lymphoid, and nonhematolymphoid markers. These findings were most consistent with PEL and erythroblastic sarcoma. RNA sequencing revealed the novel NFIA-RUNX1T1 fusion.Conclusions: Along with the previously reported PELs with NFIA-CBFA2T3 fusions, we describe a subset of PELs that occur in children, that frequently display extramedullary disease, and that harbor rearrangements of NFIA with core binding factor genes. We hypothesize that, together, these cases represent a rare but distinct clinicopathologic group of pediatric PELs with recurrent genetic abnormality. [ABSTRACT FROM AUTHOR]

Purpose of the Review: Acute erythroleukemia (AEL) is a rare form of acute myeloid leukemia recognized by erythroblastic proliferation. Many controversies remain around diagnosis influencing prognostic and therapeutic implications relating to this unique leukemia subset. Recent Findings: The 2016 WHO classification includes more clear and restrictive diagnostic criteria for AEL. Primary acute erythroid leukemia is associated with complex and high-risk karyotypes including chromosomes 5q and 7q abnormalities. Mutational data shows that AEL is characterized by far lower NPM1 and FLT3-ITD mutation rates and higher mutational rates in TP53 compared with other AML subtypes. Hypomethylating agents have shown therapeutic value in AEL. Summary: In this article, we discuss the evolving diagnostic concepts of erythroleukemia, genomics, clinical outcome, and promising therapeutic targets through an appraisal of the current literature. [ABSTRACT FROM AUTHOR]

Acute erythroid leukemia (AEL) is a subtype of Acute Myeloid Leukemia (AML), comprising less than 5% of AML cases, characterized by erythroblastic proliferation. It's a rare and aggressive form of acute leukemia whose biology remains poorly described, and there are many controversies around diagnosis influencing prognostic and therapeutic challenges. The average survival time for this type of Leukemia is 3 months. We present a unique case of a patient already known to have Chronic Kidney Disease stage G4, diagnosed with Acute Erythroid Leukemia (Fab M6), confirmed by Flow-Cytometry (infiltration of 93% erythroblasts in the Bone Marrow), who underwent specific chemotherapy (Azacitidine and Venetoclax) for 4 months. Due to severe pancytopenia and the presence of leukemic hiatus, it was challenging to avoid hemodialysis/hemofiltration, overcome metabolic acidosis and hyperuricemia, preserve serum creatinine levels at acceptable levels, and maintain hydroelectrolytic balance. All drug dosages (chemotherapy and supportive treatment) were adapted to the patient's renal function. [ABSTRACT FROM AUTHOR]

E-cadherin is expressed in hematopoietic erythroid precursors, but to our knowledge, its expression in blastic plasmacytoid dendritic cell neoplasm (BPDCN) has not been described. We report a case of BPDCN showing strong expression of E-cadherin, arising in a patient with history of primary myelofibrosis. Four more cases of BPDCN tested all showed strong expression of E-cadherin. Lack of awareness of this pattern of expression may lead to erroneous diagnosis of acute erythroid leukemia. It is increasingly becoming important to correctly identify this group of neoplasms, as approved new anti-CD123–targeted therapies are becoming available. [ABSTRACT FROM AUTHOR]

Quizartinib is an FMS‐like tyrosine kinase 3 (FLT3) inhibitor that has shown robust clinical activity in patients with FLT3‐internal tandem duplication–mutated relapsed/refractory acute myeloid leukemia (AML). This analysis evaluated the population pharmacokinetics (PK) of quizartinib and its active metabolite, AC886, in a pooled analysis of data from 649 healthy volunteers or patients with AML from 8 clinical trials including the phase 3 QuANTUM‐R study. Quizartinib was given as a single dose or multiple once‐daily doses of 20, 30, 60, or 90 mg. Nonlinear mixed‐effects modeling was performed using observed concentrations of quizartinib and AC886. Strong CYP3A inhibitor use resulted in an 82% increase in the area under the curve (AUC) and a 72% increase in the maximum concentration (Cmax) of quizartinib. Albumin level, age, and body surface area were statistically significant covariates on quizartinib PK. However, their individual effects on quizartinib AUC and Cmax were <20%. For AC886, strong CYP3A inhibitor use, body surface area and black/African American race were significant covariates. Except for strong CYP3A inhibitor use, the effects on the overall exposure (AUC of quizartinib + AC886) were <20%. The population PK model provided an adequate description of the observed concentrations of quizartinib and AC886 in both healthy volunteers and patients with AML. Only concomitant use of strong CYP3A inhibitors had a clinically meaningful effect on quizartinib PK exposure. [ABSTRACT FROM AUTHOR]

Keywords: acute erythroid leukemia; AML-M6b; EPOR; ERG; chromosome 19p13 EN acute erythroid leukemia AML-M6b EPOR ERG chromosome 19p13 e174 e177 4 05/19/20 20200515 NES 200515 Acute erythroid leukaemia (AEL) is a particular form of acute myeloid leukaemia (AML). We found one I TP53 i -mutated M6a case (HD-2702) with CNA of I EPOR i and of the I ERG i gene at 21q22.3 (Fig S1). Thus, AEL may result from mutations in common cancer genes and in specific red blood cell genes. ACGH analysis of M6a-AEL HD-2702 and M6b-AEL HD-2771 cases. [Extracted from the article]

Myelodysplastic syndrome (MDS) that evolves into acute leukemia with blasts of mixed phenotypes has rarely been reported and has no distinct diagnostic category. Herein, we describe a 79-year-old Korean female patient with MDS–excess blasts (MDS-EB) that evolved into acute leukemia; the blasts simultaneously expressed B-lymphoid and myeloid antigens. The patient was diagnosed with MDS-EB with blasts of myeloid lineage coexpressing a few B-lymphoid antigens with 7q and 20q abnormalities. The disease progressed to acute leukemia with blasts carrying more B-lymphoid antigens, which was immunophenotypically compatible with B-lymphoid/myeloid acute leukemia. Unlike previously reported patients whose blast populations are bilineal, our patient is the first with biphenotypic acute leukemia that progressed from MDS. The diagnosis of our patient introduces the possibility that many other types of biphenotypic acute leukemia may have gone undiagnosed and encourages hematologists to designate a specific diagnostic category for this type of disease, so that it can more readily be detected and studied in the future. [ABSTRACT FROM AUTHOR]

A series of novel parthenolide–thiazolidinedione hybrids have been synthesized via a click chemistry-mediated coupling between parthenolide and thiazolidinedione, and evaluated for their cytotoxic activities. The results indicated that all the hybrids showed moderate cytotoxic effects on human cancer cell lines, including human erythroleukemia cell line (HEL), prostate (PC3), and breast (MDA-MB-231) by MTT assay. In particular, compound VI-6 exhibited the best cytotoxic activities against the MDA-MB-231 cells with IC50 value of 2.07 µM, which was about eight times more active than that of the original compound (PTL). These interesting results might be used to develop novel lead scaffolds for potential anticancer agents. [ABSTRACT FROM AUTHOR]

Summary: Splicing of pre-mRNA into functional mRNA, carried out by the spliceosome, represents a crucial step in eukaryotic gene expression. Mutations and other deregulation in some of the spliceosome components have been identified in multiple pathologies, including hematological malignancies. In this context, we evaluated the therapeutic potential of a splicing inhibitor, Pladienolide B (Pla-B), in two erythroleukemia cell lines. HEL and K562 cell lines were incubated with increasing doses of Pla-B in single and daily administration. Cell viability and density were evaluated using trypan blue assay. Flow cytometry was used to evaluate cell death, cell cycle, and caspase activity. NGS analysis was performed to assess the mutational status of 4 splicing-related genes (SF3B1, U2AF1, ZRSR2 and SRSF2). Expression levels of SF3B1 and unspliced DNAJB1 were evaluated by qPCR. Pla-B significantly decreased the viability and proliferation of both cell lines in time, dose, administration schedule, and cell line-dependent manner. HEL cells were more sensible to Pla-B (IC50 = 1.5 nM) than K562 (IC50 = 25 nM), with an IC50 almost 17 times lower. Pla-B induced cell death, mainly by apoptosis, and cell cycle arrest in G0/G1 phase. No mutations were found in any of the analyzed genes, suggesting that the observed cytotoxic effect is independent of the spliceosome mutations. Splicing modulator Pla-B showed high antitumor activity against HEL and K562 cell lines, inducing apoptosis and cell cycle arrest. These data suggest that Pla-B might represent a new therapeutic approach for erythroleukemia. [ABSTRACT FROM AUTHOR]

Abstract Background The incidence of acute erythroid leukemia subtype (AEL) is rare, accounting for 5% of cases of acute myeloid leukemia (AML), and the outcome is dismal. However, in 2016 revision to the WHO classification, the subcategory of AEL has been removed. Myeloblasts are redefined as the percentage of total marrow cells, not non-erythroid cells. Therefore, the previously diagnosed AEL cases are currently diagnosed as AML or myelodyspalstic syndrome (MDS) according to new criteria. Methods We respectively reviewed cases of 97 de novo previously diagnosed AEL and all the patients were diagnosed as AML or MDS according to the new classification scheme, and then the clinical characteristics of these two subtypes were compared. Statistical analyses were performed by SPSS software version 18.0. Results The median age was 37 years-old, the two-thirds of previous AEL cases were diagnosed as MDS, and there was no obvious difference between two subtypes except for male/female ratio and age. Cytogenetic, rather than MDS/AML subtypes, can better represent the prognostic factor of previously diagnosed AEL patients. When the cytogenetic risk of patients belonged to MRC intermediate category and age were below 40 years-old in previous AEL cases, the patients who received induction chemotherapy without transplantation had a similar survival compared with the patients who underwent transplantation (3-year OS: 67.2% vs 68.5%). Conclusions Cytogenetic, rather than MDS/AML subtypes, can better represent the prognostic factor of previously diagnosed AEL patients. Transplantation was a better choice for those whose cytogenetic category was unfavorable.

Dacogen, the formulated product of the pharmaceutically active agent decitabine (5 aza‐2′‐deoxycytidine), is approved for treatment of myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML). The current analysis was performed to characterize the pharmacokinetics of decitabine in pediatric patients with AML and evaluate their consistency with the PK in adult patients. A population pharmacokinetic model was developed by pooling decitabine concentration‐time data from 5 adult (AML and MDS) and 2 pediatric (AML) studies. A total of 840 concentration‐time data points obtained from 71 adults and 28 pediatric subjects (1 to 16 years old) were available for analysis. A 2‐compartment linear pharmacokinetic (PK) model with allometric scaling using body surface area accounting for body size adequately described the PK of decitabine. After accounting for body size, decitabine pharmacokinetics were not affected by age, sex, race, dosing regimen, renal function (creatinine clearance), bilirubin, or disease type (AML or MDS) and all PK parameters (including clearance, steady‐state volume of distribution, maximum concentration, time to reach maximal concentration, and terminal half‐life) were comparable between adult and pediatric patients. Simulated concentration‐time profiles using the final population PK model suggested that decitabine exposure at steady state was similar in adults and pediatrics for a 20 mg/m2 decitabine dose administered as a 1‐hour infusion once daily. The current analysis suggests that decitabine PK is similar in pediatric AML patients and a combined adult AML and MDS population. [ABSTRACT FROM AUTHOR]

Non-adherent cells play key roles in various biological processes. Studies on this type of cell, especially at single-cell resolution, help reveal molecular mechanisms underlying many biological and pathological processes. The emerging microfluidics technology has developed effective methods for analyzing cells. However, it remains challenging to treat and monitor single live non-adherent cells in an in situ, long-term, and real-time manner. Herein, a microfluidic platform was set up to generate and anchor cell-laden water-in-oil-in-water (W/O/W) double emulsions (DEs) to investigate these cells. Within the device, W/O/W DEs encapsulating non-adherent cells were generated through two adjacent flow-focusing structures and subsequently anchored in an array of microchambers. These droplets maintained the W/O/W structure and the anchorage status in the continuous perfusion fluid for at least one week. The mass transfer of different molecules with suitable molecular weights and partition coefficients between the interior and exterior of W/O/W DEs could be regulated by perfusion fluid flow rates. These features endow this platform with potential to continuously supply encapsulated non-adherent cells with nutrients or small-molecule stimuli/drugs through fluid perfusion. Meanwhile, the confinement of cells in the anchored DEs favored long-term monitoring of cellular dynamic behaviors and responses. As a proof of concept, fluorescein diacetate (FDA) was employed to visualize the cellular uptake and biochemical metabolism of TF-1 human erythroleukemia cells. We believe that this W/O/W DE anchorage and perfusion platform would benefit single-cell-level studies as well as small-molecule drug discovery requiring live non-adherent cells. [ABSTRACT FROM AUTHOR]

A simple, efficient and atom-economic method has been developed for the synthesis of complex alkaloid-like compounds with spiro-fused indolo[2,1-b]quinazoline and cyclopropa[a]pyrrolizine or 3-azabicyclo[3.1.0]hexane moieties. We have found that one-pot, threecomponent 1,3-dipolar cycloaddition reactions allow the desired products to be obtained from various cyclopropene derivatives with tryptanthrin-derived azomethine ylides generated in situ, in good to high yields and excellent diastereoselectivity. The possibility of ylide generation was exemplified by using α-amino acids (L-proline, L-4-thiazolidincarboxylic acid) and simplest peptides (dipeptide Gly-Gly, tripeptide Gly-Gly-Gly). Quantum chemical investigations indicate that the reaction proceeds through the S-shaped azomethine ylide, the interaction of which with cyclopropenes proceeds via a less sterically hindered endotransition state. The antitumor activity of some of spiro-tryptanthrin derivatives against erythroleukemia (K562), cervical carcinoma (HeLa) and colon carcinoma (CT26) cell lines was evaluated in vitro by MTS-assay. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to investigate if stimulating auto-paracrine muscarinic receptor signalling pathway could change human erythroleukemia K562 cell proliferation and caspase 3, 8 and 9 expression levels. To better understand the role of muscarinic receptors in cell signalling mechanism, we investigated the effects of several compounds on human erythroleukemia K562 cell proliferation and caspase 3, 8 and 9 expression. These compounds were M3 muscarinic receptor agonist, pilocarpine, pro-inflammatory cytokine, tumor necrosis factor (TNF)-alpha, and the wortmannin which is a phosphoinositide 3-kinase inhibitor. Materials and Methods: Cell proliferation and cell viability were evaluated by the trypan blue exclusion test and 5-Bromo-2-deoxy-uridine (BrdU) Labelling and Detection Kits. Caspase 3, 8 and 9 expression levels were determined by immunoblot analysis. Results: Both pilocarpine and TNF-alpha caused a small increase in human erythroleukemia K562 cell proliferation. However, when all the compounds were treated together, proliferation of human erythroleukemia K562 cells increased significantly when compared to untreated control cells. TNF-alpha and wortmannin treatment increased caspase 3 and caspase 8 expression patterns significantly in human erythroleukemia K562 cells. TNF-alpha and wortmannin treatment increased caspase 9 expression level (P>0.05) but it was not significant. Conclusion: These findings partly demonstrated that M3 muscarinic receptor mediated an increase in K562 cell proliferation. Pilocarpine prevented TNF-alpha and wortmannin induced caspase 3 and 8 expression and indirectly showed apoptosis in human erythroleukemia K562 cells. [ABSTRACT FROM AUTHOR]

Chronic myelogenous leukemia (CML) is a myeloproliferative disorder where over a period of time 15–20% of patients show blastic transformation with majority transforming into acute myeloid leukemia, most of which are of granulocytic lineage. Erythroid blast phase of CML is relatively rare with the incidence ranging from 0–10%. Further the incidence of acute erythroid leukemia by itself is fairly low amongst all acute leukemias. We report a case of 41-year-old patient with CML who failed to achieve cytogenetic remission, transformed to acute erythroid leukemia and eventually succumbed to the disease over a short period of time. Related literature is also reviewed

Acute Erythroid Leukemia (AEL) / Acute Myeloid Leukemia M6 (AML M6) is a rare disorder of hematopoietic system and accounts for 1-3% of acute leukemia and 15% of myeloid leukemia. It is characterized by uncontrolled proliferation of erythroblasts and myeloblasts. We report a case in a 70 year lady who presented with non classical symptoms and the diagnosis is based on purely peripheral smear, bone marrow findings and cytochemistry. The present case is a testament not only for rarity of disease but also a reminder that erythroleukemia can present in non-classical manner

A case study of 4-year-old girl is presented with one-week history of painless swelling in the posterior region of her right leg. Topics include examines the blood count was unremarkable: haemoglobin, platelets and white blood cells and peripheral blood smear showed left shift and blast and considered lactate dehydrogenase.

The article presents a case study related to 12-year-old boy was admitted to our hospital because of fever in April 2019. Topics include Bundles of Auer rods in immature granulocytes such as blasts or promyelocytes usually offer a morphologic clue to the diagnosis of acute promyelocytic leukemia, and the faggot cells, leukemic cells with bundles of Auer rods, can be seen in nonpromyelocytic acute myeloid leukemia (AML).

The authors explore and summarize the literature on the administration of selected inpatient chemotherapy regimens for the treatment of hematologic malignancies. The authors also offer a guide on a stepwise approach to transition the delivery of such regimens to the ambulatory care setting. Factors that make the delivery of certain regimens in the inpatient setting preferable are mentioned. HiDAC is considered a post-remission treatment approach for treating acute myeloid leukemia.

Protein arginine methyltransferase 5 (PRMT5) is a member of the arginine methyltransferase protein family that critically mediates the symmetric dimethylation of Arg-3 at histone H4 (H4R3me2s) and is involved in many key cellular processes, including hematopoiesis. However, the post-translational modifications (PTMs) of PRMT5 that may affect its biological functions remain less well-understood. In this study, using MS analyses, we found that PRMT5 itself is methylated in human erythroleukemia Lys-562 cells. Biochemical assays revealed that coactivator-associated arginine methyltransferase 1 (CARM1) interacts directly with and methylates PRMT5 at Arg-505 both in vivo and in vitro. Substitutions at Arg-505 significantly reduced PRMT5's methyltransferase activity, decreased H4R3me2s enrichment at the γ-globin gene promoter, and increased the expression of the γ-globin gene in Lys-562 cells. Moreover, CARM1 knockdown consistently reduced PRMT5 activity and activated γ-globin gene expression. Importantly, we show that CARM1-mediated methylation of PRMT5 is essential for the intracellular homodimerization ofPRMT5to its active form. These results thus reveal a critical PTM of PRMT5 that represses human γ-globin gene expression.Weconclude that CARM1-mediated asymmetric methylation of PRMT5 is critical for its dimerization and methyltransferase activity leading to the repression of γ-globin expression. Given PRMT5's crucial role in diverse cellular processes, these findings may inform strategies for manipulating its methyltransferase activity for managing hemoglobinopathy or cancer. [ABSTRACT FROM AUTHOR]

Leukemia is a hematologic malignancy with poor prognosis in humans and chemotherapy is the main strategy for treating leukemia patients. Novel drugs with better selectivity and lower toxicity are required for the treatment of patients. A novel 3’,5’-diprenylated chalcone, (E)-1-(2-hydroxy-4-methoxy-3,5-diprenyl) phenyl-3-(3- pyridinyl)-propene-1-one ( C10 ) is a potential new anti-leukemia agent. In this study, we investigated the molecular mechanisms of the anti-leukemia effects of C10 on different leukemia cells in vitro . C10 showed strong inhibition of proliferation of the human erythroleukemia cell line HEL and human myeloid leukemia cell line K562, and several cell and flow cytometer assays showed that inhibition by C10 was due to the regulation of gene expression or phosphorylation in the apoptosis and autophagy pathways. The results showed that C10 regulated the expression of Bax, c-Myc, Bcl-2, P38/AMPK and ERK 1/2, activated the expression of Caspase-3, -8, and PARP at the protein level in the apoptosis pathway of the two leukemia cell types, and inhibited the expression of erythroleukemia carcinogene Fli-1 in the human erythroleukemia cell line HEL. Additionally,treatment with the compound induced a time-dependent increase in expression of LC 3A/B via inhibiting the AKT-mTOR pathway, which is associated with cell autophagy. Taken together, the above results suggest that the novel synthesized 3’,5’-diprenylated chalcone can prevent the growth of leukemia cells by inducing apoptosis and autophagy. [ABSTRACT FROM AUTHOR]

The phenotype of multidrug resistance (MDR) is one of the main causes of chemotherapy failure. Our study investigated the effect of C-phycocyanin (C-PC) in three human erythroleukemia cell lines with or without the MDR phenotype: K562 (non-MDR; no overexpression of drug efflux proteins), K562-Lucena (MDR; overexpression of ATP-binding cassette, sub-family B/ABCB1), and FEPS (MDR; overexpression of ABCB1 and ATP-binding cassette, sub-family C/ABCC1). Using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, we showed that 20 and 200 μg/mL C-PC decreased K562 viable cells after 24 h and 200 μg/mL C-PC decreased K562-Lucena cell proliferation after 48 h. C-PC did not decrease viable cells of FEPS cells. On the other hand, the MTT assay showed that exposure of 2, 20, and 200 μg/mL C-PC for 24 or 48 h was not cytotoxic to peritoneal macrophages. At 72 h, the trypan blue exclusion assay showed that 20 μg/mL C-PC decreased K562 and K562-Lucena cell proliferation and in FEPS cells, only 200 μg/mL C-PC decreased proliferation. In addition, protein–protein docking showed differences in energy and binding sites of ABCB1 and ABCC1 for C-PC, and these results were confirmed by the efflux protein activity assay. Only ABCC1 activity was altered in the presence of C-PC and FEPS cells showed lower C-PC accumulation, suggesting C-PC extrusion by ABCC1, conferring C-PC resistance. In combination with chemotherapy (vincristine [VCR] and daunorubicin [DNR]), the sensitivity of K562-Lucena cells for C-PC + VCR did not increase, whereas FEPS cell sensitivity for C-PC + DNR was increased. In molecular docking experiments, the estimated free energies of binding for C-PC associated with chemotherapy were similar (VCR: -6.9 kcal/mol and DNR: -7.2 kcal/mol) and these drugs were located within the C-PC cavity. However, C-PC exhibited specificity for tumor cells and K562 cells were more sensitive than K562-Lucena cells, followed by FEPS cells. Thus, C-PC is a possible chemotherapeutic agent for cells with the MDR phenotype, both alone in K562-Lucena cells (resistance due to ABCB1), or in combination with other drugs for cells similar to FEPS (resistance due to ABCC1). Moreover, C-PC did not damage healthy cells (peritoneal macrophages of Mus musculus ). [ABSTRACT FROM AUTHOR]

Background Although a number of risk factors have been associated with invasive fungal disease (IFD), a systematic review of the literature to document pediatric-specific factors has not been performed. Methods We used the Ovid SP platform to search Medline, Medline In-Process, and Embase for studies that identified risk factors for IFD in children with cancer or those who undergo hematopoietic stem cell transplantation (HSCT). We included studies if they consisted of children or adolescents (<25 years) who were receiving treatment for cancer or undergoing HSCT and if the study evaluated risk factors among patients with and those without IFD. Results Among the 3566 studies screened, 22 studies were included. A number of pediatric factors commonly associated with an increased risk for IFD were confirmed, including prolonged neutropenia, high-dose steroid exposure, intensive-timing chemotherapy for acute myeloid leukemia, and acute and chronic graft-versus-host disease. Increasing age, a factor not commonly associated with IFD risk, was identified as a risk factor in multiple published cohorts. Conclusions With this systematic review, we have confirmed IFD risk factors that are considered routinely in daily clinical practice. Increasing age should also be considered when assessing patient risk for IFD. Future efforts should focus on defining more precise thresholds for a particular risk factor (ie, age, neutropenia duration) and on development of prediction rules inclusive of individual factors to further refine the risk prediction. [ABSTRACT FROM AUTHOR]

Background: Zingiber zerumbet locally known as lempoyang is used traditionally to cure swelling, sores, and loss of appetite. Its rhizomes contain many active compounds such as zerumbone and kaempferol that have been shown to exhibit antiproliferative activities on various cancer cell types. However, the effect of this plant on leukemia has not thoroughly been investigated. Objective: This study was conducted to investigate the cytotoxic effects of Z. zerumbet ethyl acetate crude extract on apoptosis-resistant erythroleukemia cell line, K-562. Materials and Methods: The cytotoxic effects and morphological changes of Z. zerumbet ethyl acetate crude extract on apoptosis-resistant erythroleukemia cell line, K-562, were investigated spectrometrically through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay and morphologically using the phase-contrast microscopy, respectively. Results: MTT assay demonstrated that this crude extract showed cytotoxic effects on erythroleukemia cell line K-562 in a dose-dependent and time-dependent manner with IC50values of 13.83 ± 1.82 and 10.13 ± 1.67 μg/ml for 48 and 72 h time points, respectively. The morphology of treated cells showed apparent changes of features such as membrane blebbing, cell shrinkage, and formation of apoptotic bodies which were the signs of apoptosis. The changes of cell morphology that resembled apoptotic features were more obvious with increase in treatment time. Conclusions: This finding indicates that ethyl acetate crude extract of Z. zerumbet exhibits cytotoxic effects on K-562 cell line through induction of apoptosis as morphologically seen in the cells. Further investigations are needed to ascertain the possibility of apoptosis as its major event of cell death. Abbreviations used: MTT: 3-(4,5-Dimethylthiazol-2-yI)-2,5-diphenyl tetrazolium bromide; DMSO: Dimethylsulfoxide; h: Hour. [ABSTRACT FROM AUTHOR]

The 2016 revision of the World Health Organization (WHO) classification of tumours of haematopoietic and lymphoid tissues was published. According to 2016 WHO criteria, diagnostic criteria of acute erythroid leukemia was revised. We reassessed 34 de novo acute erythroid leukemia (AEL) diagnosed by 2008 WHO criteria, according to 2016 WHO criteria. A total of 623 patients (excluding M3) with acute myeloid leukemia including 34 patients with AEL were enrolled. Among 34 patients diagnosed with AEL, diagnosis was shifted to MDS-EB in 28 patients (28/34, 82.3%) and MDS-U in 2 patients (2/34, 5.9%), while remained as AEL in 4 patients (4/34, 11.8%) according to 2016 WHO criteria. Interphase FISH for cytogenetic changes of MDS (-5/del(5q), −7/del(7q), del(20q), +8) revealed cytogenetic aberrations in 50.0% (17/34) of AEL 2008 group. AEL 2008 group showed higher frequency of complex cytogenetic abnormalities and higher MDS related cytogenetic abnormalities than AML excluding AEL group. Transformation to another AML subtype was noted in 10% in AEL shifted to MDS. Majority (88.2%) of AEL by 2008 WHO criteria was reclassified to MDS by 2016 WHO criteria. Clinical characteristics of shifted AEL were similar to those of MDS rather than de novo AML. [ABSTRACT FROM AUTHOR]

Background Recent studies have introduced Pleurotus ostreatus (Pleurotaceae) as a herbal medicine for treating different types of cancer. This survey utilizes P. ostreatus and doxorubicin hydrochloride (DOX) alone and then with hyperthermia to investigate the erythroleukemia cell line. This study evaluates and compares the apoptotic and necrotic effects of various treatments on the KG-1 cell line. Methods The proliferation of KG-1 cells was measured by using a tetrazolium salt (MTT)-based colorimetric assay during 96 h after treatment by gradient dilutions of 100 ng/mL to 100 mg/mL of P. ostreatus methanol extract and then the minimum inhibitory concentration (MIC) was determined and was applied in additional experiments. Afterward, the cells were treated using P. ostreatus extract, DOX (6.95 mg/L), and hyperthermia (42 and 44 °C), separately and then applying hyperthermia. Finally, the ratios of apoptosis and necrosis after 24 h incubation were evaluated by using flow cytometry. Results The MIC of the extract was determined (1 mg/mL), which significantly increased the ratio of apoptosis rather than necrosis, whereas the DOX treatment primarily induced necrosis on the KG-1 cells. The anticancer effects of the mushroom extract were significantly increased when it was combined with thermotherapy, which exhibited apoptotic effects at 42 °C but induced necrosis at 44 °C. Conclusions The results suggest that P. ostreatus extract induces apoptosis on KG-1 cells and its anticancer effects are significantly increased in combination with thermotherapy. Therefore, P. ostreatus could be considered as an alternative with anticancer effect for further studies in erythroleukemia patients. [ABSTRACT FROM AUTHOR]

NF90 and splice variant NF110 are DNA- and RNA-binding proteins encoded by the Interleukin enhancer-binding factor 3 (ILF3) gene that have been established to regulate RNA splicing, stabilization and export. The roles of NF90 and NF110 in regulating transcription as chromatin-interacting proteins have not been comprehensively characterized. Here, chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) identified 9,081 genomic sites specifically occupied by NF90/NF110 in K562 cells. One third of NF90/NF110 peaks occurred at promoters of annotated genes. NF90/NF110 occupancy colocalized with chromatin marks associated with active promoters and strong enhancers. Comparison with 150 ENCODE ChIP-seq experiments revealed that NF90/NF110 clustered with transcription factors exhibiting preference for promoters over enhancers (POLR2A, MYC, YY1). Differential gene expression analysis following shRNA knockdown of NF90/NF110 in K562 cells revealed that NF90/NF110 activates transcription factors that drive growth and proliferation (EGR1, MYC), while attenuating differentiation along the erythroid lineage (KLF1). NF90/NF110 associates with chromatin to hierarchically regulate transcription factors that promote proliferation and suppress differentiation. [ABSTRACT FROM AUTHOR]