Treatment Of Leukemia Research Articles

Assessment of the in Vitro Effects of Folate Core-Shell Conjugated Iron Oxide Nanoparticles as a Potential Agent for Acute Leukemia Treatment.

There is a growing need to comprehend the potential outcomes of nanoparticles (NPs) on human well-being, including their potential for detecting and treating leukemia. This study examined the role of iron folate core-shell and iron oxide nanoparticles in inducing apoptosis and altering the expression of the B-cell lymphoma 2 (Bcl-2), Bcl-2 associated X-protein (Bax), and Caspase-3 genes in leukemia cells. The obtained iron oxide and iron folate core-shell nanoparticles were analyzed using a variety of analytical techniques, including ultraviolet-visible (UV-Vis) absorption spectroscopy, Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), dynamic light scattering (DLS), zeta potential, and transmission electron microscopy (TEM). Additionally, FTIR and UV-Vis were used to characterize doxorubicin. The MTT test was utilized to investigate the cytotoxicity of iron oxide and iron folate core-shell nanoparticles. The expression of the apoptotic signaling proteins Bcl-2, Bax, and Caspase-3 was evaluated using the real-time reverse transcription polymerase chain reaction (RT-qPCR) method. Additionally, flow cytometry was performed to gauge the degrees of necrosis and apoptosis. UV-Visible spectroscopy analysis showed that the generated iron oxide and iron folate core-shell NPs had a distinctive absorption curve in the 250-300 nm wavelength range. The XRD peaks were also discovered to index the spherical form with a size of less than 50 nm, which validated the crystal structure. The FTIR analysis determined the bonds and functional groups at wavenumbers between 400 and 4000 cm-1. A viable leukemia treatment approach is a nanocomposite consisting of iron and an iron folate core-shell necessary for inhibiting and activating cancer cell death. The nearly resistant apoptosis in the CCRF-CEM cells may have resulted from upregulating Bax and Casepase-3 while downregulating Bcl-2 expression. Our study documents the successful synthetization and characterization of iron oxide, which has excellent anticancer activities. A metal oxide conjugation with the nanoparticles' core-shell enhanced the effect against acute leukemia.

Systems Biology for Drug Target Discovery in Acute Myeloid Leukemia.

Combining new therapeutics with all-trans-retinoic acid (ATRA) could improve the efficiency of acute myeloid leukemia (AML) treatment. Modeling the process of ATRA-induced differentiation based on the transcriptomic profile of leukemic cells resulted in the identification of key targets that can be used to increase the therapeutic effect of ATRA. The genome-scale transcriptome analysis revealed the early molecular response to the ATRA treatment of HL-60 cells. In this study, we performed the transcriptomic profiling of HL-60, NB4, and K562 cells exposed to ATRA for 3-72 h. After treatment with ATRA for 3, 12, 24, and 72 h, we found 222, 391, 359, and 1032 differentially expressed genes (DEGs) in HL-60 cells, as well as 641, 1037, 1011, and 1499 DEGs in NB4 cells. We also found 538 and 119 DEGs in K562 cells treated with ATRA for 24 h and 72 h, respectively. Based on experimental transcriptomic data, we performed hierarchical modeling and determined cyclin-dependent kinase 6 (CDK6), tumor necrosis factor alpha (TNF-alpha), and transcriptional repressor CUX1 as the key regulators of the molecular response to the ATRA treatment in HL-60, NB4, and K562 cell lines, respectively. Mapping the data of TMT-based mass-spectrometric profiling on the modeling schemes, we determined CDK6 expression at the proteome level and its down-regulation at the transcriptome and proteome levels in cells treated with ATRA for 72 h. The combination of therapy with a CDK6 inhibitor (palbociclib) and ATRA (tretinoin) could be an alternative approach for the treatment of acute myeloid leukemia (AML).

Self-Stimulated Photodynamic Nanoreactor in Combination with CXCR4 Antagonists for Antileukemia Therapy.

The treatment of acute myeloid leukemia (AML) remains unsatisfactory, owing to the absence of efficacious therapy regimens over decades. However, advances in molecular biology, including inhibiting the CXCR4/CXCL12 biological axis, have introduced novel therapeutic options for AML. Additionally, self-stimulated phototherapy can solve the poor light penetration from external sources, and it will overcome the limitation that traditional phototherapy cannot be applied to the treatment of AML. Herein, we designed and manufactured a self-stimulated photodynamic nanoreactor to enhance antileukemia efficacy and suppress leukemia recurrence and metastasis in AML mouse models. To fulfill our design, we utilized the CXCR4/CXCL12 biological axis and biomimetic cell membranes in conjunction with self-stimulated phototherapy. This nanoreactor possesses the capability to migrate into the bone marrow cavity, inhibit AML cells from infiltrating into the visceral organ, significantly enhance the antileukemia effect, and prolong the survival time of leukemic mice. Therefore, this nanoreactor has significant potential for achieving high success rates and low recurrence rates in leukemia treatment.

Tongue cancer developing after haematopoietic stem cell transplantation for treatment of acute promyelocytic leukaemia: a case report

Acute promyelocytic leukaemia (APL) is a form of acute myelogenous leukaemia. APL is characterised by anaemia due to suppression of normal haematopoiesis and infection. Haematopoietic stem cell transplantation (HSCT) is current option for the treatment of haematopoietic malignancies and is proving to be successful. Although HSCT has been effective for the treatment of haematopoietic malignant tumours, chronic graft-versus-host disease (GVHD) but secondary cancers can occur, which is a serious complication and frequently involves the oral cavity and skin. Here, we report the case of tongue cancer occurring 17 years after transplantation in a patient who developed GVHD after haematopoietic stem cell transplantation and APL remission. To the best of our knowledge, this is the first report of secondary oral cancer after HSCT with APL as the primary disease. Keywords: Chronic graft versus host disease, Haematopoietic stem cell transplantation, Oral squamous cell carcinoma, Secondary cancer.

Quality of life in children and adolescents after treatment for acute lymphoblastic leukemia according to the NOPHO ALL2008 protocol.

The improved outcome of childhood acute lymphoblastic leukemia (ALL) over the last decades has increased the importance of assessing late effects and health-related quality of life (HRQoL), particularly when evaluating and comparing outcomes in clinical trials. This study aimed to assess HRQoL in children treated for ALL according to the NOPHO ALL2008 protocol. Children, aged 1 to less than 18years at diagnosis, alive in first remission, and their parents, were asked to complete PedsQL 4.0 Generic Core Scales (self- and proxy-report) at ≥6months after end of therapy. Data on socioeconomic factors and parent-reported toxicity were collected through a study-specific questionnaire, and the NOPHO ALL2008 database was used to identify eligible families and add additional disease- and treatment-related data. HRQoL data were collected during 2013-2019 in Sweden, Finland, and Denmark. A total of 299 children were included. The older children (8years and older) reported similar HRQoL scores compared to Finnish reference data, except lower scores for School Functioning in high-risk patients. Scores from the parent-proxy and self-reports from 5-7-year olds were notably lower than reference. Parent-reported toxicity was associated with lower total and physical HRQoL scores in adjusted models for younger as well as older children in the self-report and parent-proxy versions, and also with lower psychosocial score in the parent-proxy. Self-reported HRQoL was similar to reference population. The most important determinant for HRQoL after end of ALL treatment was parent-reported toxicity during treatment. Thus, minimizing complications is an obvious focus for future treatment protocols.

Assessment of structural and activity-related contributions of various PIM-1 kinase inhibitors in the treatment of leukemia and prostate cancer.

One of the most perilous illnesses in the world is cancer. The cancer may be associated with the mutation of different genes inside the body. The PIM kinase, also known as the serine/threonine kinase, plays a critical role in the biology of different kinds of cancer. They are widely distributed and associated with several biological processes, including cell division, proliferation, and death. Aberration of PIM-1 kinase is found in varieties of cancer. Prostate cancer and leukemia can both be effectively treated with PIM-1 kinase inhibitors. There are several potent compounds that have been explored in this review based on heterocyclic compounds for the treatment of prostate cancer and leukemia that have strong effects on the suppression of PIM-1 kinase. The present review summarizes the PIM-1 kinase pathway, their inhibitors under clinical trial, related patents, and SAR studies of several monocyclic, bicyclic, and polycyclic compounds. The study related to their molecular interactions with receptors is also included in the present manuscript. The study may be beneficial to scientists for the development of novel compounds as PIM-1 inhibitors in the treatment of prostate cancer and leukemia.

Interaction of olive oil-based propolis and caffeic acid phenethyl ester with methylprednisolone used in the treatment of human acute myeloid leukemia.

Methylprednisolone (MP) is a pharmaceutical agent employed in the management of Leukemia, which is a systemic malignancy that arises from abnormalities in the hematological system. Numerous investigations in the field of cancer research have directed their attention towards propolis, a natural substance with significant potential as a treatment-supportive agent. Its utilization aims to mitigate the potential adverse effects associated with chemotherapy medications. The objective of this study was to examine the impact of olive oil-based propolis (OEP) and caffeic acid phenethyl ester (CAPE) on the treatment of acute myeloid leukemia, as well as to determine if they exhibit a synergistic effect when combined with the therapeutic support product methylprednisolone. The proliferation of HL-60 cells was quantified using the WST-8 kit. The PI Staining technique was employed to do cell cycle analysis of DNA in cells subjected to OEP, CAPE, and MP, with subsequent measurement by flow cytometry. The apoptotic status of cells was determined by analyzing them using flow cytometry after staining with the Annexin V-APC kit. The quantification of apoptotic gene expression levels was conducted in HL-60 cells. In HL-60 cells, the IC50 dosages of CAPE and MP were determined to be 1 × 10- 6 M and 5 × 10- 4 M, respectively. The HL-60 cells were subjected to apoptosis and halted in the G0/G1 and G2/M phases of the cell cycle after being treated with MP, CAPE, and OEP. Propolis and its constituents have the potential to serve as effective adjunctive therapies in chemotherapy.

T-Cell Engagers-The Structure and Functional Principle and Application in Hematological Malignancies.

Recent advancements in cancer immunotherapy have made directing the cellular immune response onto cancer cells a promising strategy for the treatment of hematological malignancies. The introduction of monoclonal antibody-based (mAbs) targeted therapy has significantly improved the prognosis for hematological patients. Facing the issues of mAb-based therapies, a novel bispecific antibody (BsAb) format was developed. T-cell engagers (TCEs) are BsAbs, which simultaneously target tumor-associated antigens on tumor cells and CD3 molecules present on T-cells. This mechanism allows for the direct activation of T-cells and their anti-tumor features, ultimately resulting in the lysis of tumor cells. In 2014, the FDA approved blinatumomab, a TCE directed to CD3 and CD19 for treatment of acute lymphoblastic leukemia. Since then, numerous TCEs have been developed, allowing for treating different hematological malignancies such as acute myeloid leukemia, multiple myeloma, and non-Hodgkin lymphoma and Hodgkin lymphoma. As of November 2023, seven clinically approved TCE therapies are on the market. TCE-based therapies still have their limitations; however, improving the properties of TCEs, as well as combining TCE-based therapies with other forms of treatment, give hope to find the cures for currently terminal diseases. In this paper, we summarized the technical basis of the TCE technology, its application in hematology, and its current issues and prospects.

INA03, a potent transferrin-competitive antibody-drug conjugate against CD71, for a safer acute leukemia treatment.

Innovative strategies to enhance efficacy and overcome drug resistance in hematologic cancers such as antibody-drug conjugates (ADCs) have shifted the paradigm of conventional care by delivering promising outcomes in cancer therapies with a significant reduction in the risk of relapse. The transferrin receptor 1, CD71, known to be overexpressed in malignant cells, is considered a potent anti-tumoral target. Therefore, we have developed an anti-CD71 ADC, INA03, a humanized antibody conjugated to the monomethyl auristatin E (MMAE) through a 3-arylpropiolonitrile-valine-citruline linker. In this study, we investigated both potency and safety of INA03, in competition with transferrin (Tf), the CD71's natural ligand, as a novel strategy to specifically target highly proliferative cells. The high expression of CD71 was confirmed on different leukemic cell lines, allowing INA03 to bind efficiently. Subsequently, INA03 rapidly internalizes into lysosomal compartments, where its cytotoxic drug is released following cathepsin-B cleavage. Downregulating CD71 expression using shRNA highlighted that INA03-induced cell death was dependent on CD71 density at the cell surface. INA03 intravenous treatment in acute leukemia mouse models significantly reduced tumor burden, increased mice survival and showed no residual disease compared to conventional chemotherapies. Since INA03 competes with the human Tf, a double knock-in (hCD71/hTf) competent mouse model was generated to mimic human pharmacokinetics and pharmacodynamics. INA03 administration in hCD71/hTf mice did not reveal, even at high doses, any improper toxicities. Hence, these data demonstrate promising pre-clinical efficacy and safety of INA03 and support its development as a novel acute leukemia treatment.

The Impact of Gut Microbiota Changes on Methotrexate-Induced Neurotoxicity in Developing Young Rats.

Methotrexate (MTX) is an essential part of therapy in the treatment of acute lymphoblastic leukemia (ALL) in children, and inferior intellectual outcomes have been reported in children who are leukemia survivors. Although several studies have demonstrated that the interaction between gut microbiota changes and the brain plays a vital role in the pathogenesis of chemotherapy-induced brain injury, preexisting studies on the effect of MTX on gut microbiota changes focused on gastrointestinal toxicity only. Based on our previous studies, which revealed that MTX treatment resulted in inferior neurocognitive function in developing young rats, we built a young rat model mimicking MTX treatment in a child ALL protocol, trying to investigate the interactions between the gut and brain in response to MTX treatment. We found an association between gut microbiota changes and neurogenesis/repair processes in response to MTX treatment, which suggest that MTX treatment results in gut dysbiosis, which is considered to be related to MTX neurotoxicity through an alteration in gut-brain axis communication.

A 2024 Update on Menin Inhibitors. A New Class of Target Agents against KMT2A-Rearranged and NPM1-Mutated Acute Myeloid Leukemia.

Menin inhibitors are new and promising agents currently in clinical development that target the HOX/MEIS1 transcriptional program which is critical for leukemogenesis in histone-lysine N-methyltransferase 2A-rearranged (KMT2Ar) and in NPM1-mutated (NPM1mut) acute leukemias. The mechanism of action of this new class of agents is based on the disruption of the menin-KMT2A complex (consisting of chromatin remodeling proteins), leading to the differentiation and apoptosis of AML cells expressing KMT2A or with mutated NPM1. To date, this new class of drugs has been tested in phase I and II clinical trials, both alone and in combination with synergistic drugs showing promising results in terms of response rates and safety in heavily pre-treated acute leukemia patients. In this brief review, we summarize the key findings on menin inhibitors, focusing on the mechanism of action and preliminary clinical data on the treatment of acute myeloid leukemia with this promising new class of agents, particularly revumenib and ziftomenib.

The Depth of the Molecular Response in Patients with Chronic Myeloid Leukemia Correlates with Changes in Humoral Immunity.

Background and Objectives: The effective treatment of chronic myeloid leukemia leads to the restoration of proper immune system function. We aimed to investigate fluctuations in circulating cytokines, angiogenic factors and complement components in patients with CML during the first year of treatment with TKI and correlate them with the degree of achieved molecular response. Material and Methods: We recruited 31 patients with newly diagnosed CML. Peripheral blood and bone marrow samples were obtained, and concentrations of serum proteins were measured using an immunology multiplex assay. Results: The study cohort was divided into two groups of optimal or non-optimal in accordance with the European Leukemia Net (ELN) guidelines. We found significantly higher concentrations of C1q, C4 and C5a in serum after 3 months of TKI treatment in patients who achieved optimal responses in the 6 months after diagnosis. The most alterations were observed during 12 months of therapy. Patients in the optimal response group were characterized by higher serum concentrations of TGF-β, EGF, VEGF, Angiopoietin 1, IFN-γ and IL-8. Conclusions: The later plasma concentrations of complement components were significantly increased in patients with optimal responses. The changes after 12 months of treatment were particularly significant. Similar changes in bone marrow samples were observed.

Discovery of a Meisoindigo-Derived PROTAC as the ATM Degrader: Revolutionizing Colorectal Cancer Therapy via Synthetic Lethality with ATR Inhibitors.

Meisoindigo (Mei) has long been recognized in chronic myeloid leukemia (CML) treatment. To elucidate its molecular target and mechanisms, we embarked on designing and synthesizing a series of Mei-derived PROTACs. Through this endeavor, VHL-type PROTAC 9b was identified to be highly cytotoxic against SW620, SW480, and K562 cells. Employing DiaPASEF-based quantitative proteomic analysis, in combination with extensive validation assays, we unveiled that 9b potently and selectively degraded ATM across SW620 and SW480 cells in a ubiquitin-proteasome-dependent manner. 9b-induced selective ATM degradation prompted DNA damage response cascades, thereby leading to the cell cycle arrest and cell apoptosis. This pioneering discovery renders the advent of ATM degradation for anti-cancer therapy. Notably, 9b-induced ATM degradation synergistically enhanced the efficacy of ATR inhibitor AZD6738 both in vitro and in vivo. This work establishes the synthetic lethality-inducing properties of ATR inhibitors in the ATM-deficient context, thereby providing new avenues to innovative therapies for colorectal cancer.

Potential New Therapies "ROS-Based" in CLL: An Innovative Paradigm in the Induction of Tumor Cell Apoptosis.

Chronic lymphocytic leukemia, in spite of recent advancements, is still an incurable disease; the majority of patients eventually acquire resistance to treatment through relapses. In all subtypes of chronic lymphocytic leukemia, the disruption of normal B-cell homeostasis is thought to be mostly caused by the absence of apoptosis. Consequently, apoptosis induction is crucial to the management of this illness. Damaged biological components can accumulate as a result of the oxidation of intracellular lipids, proteins, and DNA by reactive oxygen species. It is possible that cancer cells are more susceptible to apoptosis because of their increased production of reactive oxygen species. An excess of reactive oxygen species can lead to oxidative stress, which can harm biological elements like DNA and trigger apoptotic pathways that cause planned cell death. In order to upset the balance of oxidative stress in cells, recent therapeutic treatments in chronic lymphocytic leukemia have focused on either producing reactive oxygen species or inhibiting it. Examples include targets created in the field of nanomedicine, natural extracts and nutraceuticals, tailored therapy using biomarkers, and metabolic targets. Current developments in the complex connection between apoptosis, particularly ferroptosis and its involvement in epigenomics and alterations, have created a new paradigm.

Inhibition of NRF2 signaling overcomes acquired resistance to arsenic trioxide in FLT3-mutated Acute Myeloid Leukemia.

De novo acute myeloid leukemia (AML) patients with FMS-like tyrosine kinase 3 internal tandem duplications (FLT3-ITD) have worse treatment outcomes. Arsenic trioxide (ATO) used in the treatment of acute promyelocytic leukemia (APL) has been reported to be effective in degrading the FLT3 protein in AML cell lines and sensitizing non-APL AML patient samples in-vitro. We have previously reported that primary cells from FLT3-ITD mutated AML patients were sensitive to ATO in-vitro compared to other non-M3 AML and molecular/pharmacological inhibition of NF-E2 related factor 2 (NRF2), a master regulator of antioxidant response improved the chemosensitivity to ATO and daunorubicin even in non FLT3-ITD mutated cell lines and primary samples.We examined the effects of molecular/pharmacological suppression of NRF2 on acquired ATO resistance in the FLT3-ITD mutant AML cell line (MV4-11-ATO-R). ATO-R cells showed increased NRF2expression, nuclear localization, and upregulation of bonafideNRF2 targets. Molecular inhibition of NRF2 in this resistant cell line improved ATO sensitivity in vitro. Digoxin treatment lowered p-AKT expression, abrogating nuclear NRF2 localization and sensitizing cells to ATO. However, digoxin and ATO did not sensitize non-ITD AML cell line THP1 with high NRF2 expression. Digoxin decreased leukemic burden and prolonged survival in MV4-11 ATO-R xenograft mice. We establish that altering NRF2 expression may reverse acquired ATO resistance in FLT3-ITD AML.

Dual targeting of glutamine and serine metabolism in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy characterized by disrupted blood cell production and function. Recent investigations have highlighted the potential of targeting glutamine metabolism as a promising therapeutic approach for AML. Asparaginases, enzymes that deplete circulating glutamine and asparagine, are approved for the treatment of acute lymphoblastic leukemia, but are also under investigation in AML, with promising results. We previously reported an elevation in plasma serine levels following treatment with Erwinia-derived asparaginase (also called crisantaspase). This led us to hypothesize that AML cells initiate the de novo serine biosynthesis pathway in response to crisantaspase treatment and that inhibiting this pathway in combination with crisantaspase would enhance AML cell death. Here we report that in AML cell lines, treatment with the clinically available crisantaspase, Rylaze, upregulates the serine biosynthesis enzymes phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase (PSAT1) through activation of the Amino Acid Response (AAR) pathway, a cellular stress response mechanism that regulates amino acid metabolism and protein synthesis under conditions of nutrient limitation. Inhibition of serine biosynthesis through CRISPR-Cas9-mediated knockout of PHGDH resulted in a ~250-fold reduction in the half-maximal inhibitory concentration (IC50) for Rylaze, indicating heightened sensitivity to crisantaspase therapy. Treatment of AML cells with a combination of Rylaze and a small molecule inhibitor of PHGDH (BI4916) revealed synergistic anti-proliferative effects in both cell lines and primary AML patient samples. Rylaze-BI4916 treatment in AML cell lines led to the inhibition of cap-dependent mRNA translation and protein synthesis, as well as a marked decrease in intracellular glutathione levels, a critical cellular antioxidant. Collectively, our results highlight the clinical potential of targeting serine biosynthesis in combination with crisantaspase as a novel therapeutic strategy for AML.

Late Adverse Effects after Treatment for Childhood Acute Leukemia

The aim of this review is to raise awareness and knowledge among healthcare professionals and policymakers about late adverse effects in survivors of childhood leukemia. With contemporary treatment, over 90% of children with acute lymphoblastic leukemia (ALL) and over 60% with acute myeloid leukemia (AML) are cured. Large cohort studies demonstrate that 20% of ALL and most AML survivors have at least one chronic health condition by 20-25 years after diagnosis. These are life-changing or threatening in some survivors and contribute to increased premature mortality. We describe the frequency, causes, clinical features, and natural history of the most frequent and severe late adverse effects in childhood leukemia survivors, including subsequent malignant neoplasms, metabolic toxicity, gonadotoxicity and impaired fertility, endocrinopathy and growth disturbances, bone toxicity, central and peripheral neurotoxicity, cardiotoxicity, psychosocial late effects, accelerated ageing and late mortality. The wide range of late effects in survivors of haemopoietic stem cell transplant is highlighted. Recent developments informing the approach to long-term survivorship care are discussed, including electronic personalized patient-specific treatment summaries and care plans such as the Survivor Passport (SurPass), surveillance guidelines and models of care. The importance of ongoing vigilance is stressed given the increasing use of novel targeted drugs with limited experience of long-term outcomes. Conclusion. It is vital to raise awareness of the existence and severity of late effects of childhood leukemia therapy among parents, patients, health professionals, and policymakers. Structured long-term surveillance recommendations are necessary to standardize follow-up care.

CNS Aspergillosis and Cryptococcosis with Cytomegalovirus Pneumonia in a Patient with Chronic Lymphocytic Leukemia Treated with Acalabrutinib.

Bruton's tyrosine kinase inhibitors (BTKis) are the preferred treatment for chronic lymphocytic leukemia (CLL). Despite their therapeutic benefits, these targeted agents have been associated with an increased risk of invasive infections. We describe a 68-year-old male who developed multiple bacterial, fungal and viral infections while on treatment with acalabrutinib. To our knowledge, this is the first reported case of concomitant CNS infections with Cryptococcus neoformans and Aspergillus fumigatus, along with cytomegalovirus (CMV) and herpes simplex virus type 1 (HSV-1) pneumonia while on acalabrutinib. This case adds to the scarce literature of fungal and bacterial infections associated with acalabrutinib, raising the suspicion that infection risk is a medication class effect for BTKis.

Asparaginase-specific basophil recognition and activation predict Asparaginase hypersensitivity in mice.

Asparaginase (ASNase) is a crucial part of acute leukemia treatment, but immune responses to the agent can reduce its effectiveness and increase the risk of relapse. Currently, no reliable and validated biomarker predicts ASNase-induced hypersensitivity reactions during therapy. We aimed to identify predictive biomarkers and determine immune cells responsible for anaphylaxis using a murine model of ASNase hypersensitivity. Our preclinical study uses a murine model to investigate predictive biomarkers of ASNase anaphylaxis, including anti-ASNase antibody responses, immune complex (IC) levels, ASNase-specific binding to leukocytes or basophils, and basophil activation. Our results indicate that mice immunized to ASNase exhibited dynamic IgM, IgG, and IgE antibody responses. The severity of ASNase-induced anaphylaxis was found to be correlated with levels of IgG and IgE, but not IgM. Basophils from immunized mice were able to recognize and activate in response to ASNase ex vivo, and the extent of recognition and activation also correlated with the severity of anaphylaxis observed. Using a multivariable model that included all biomarkers significantly associated with anaphylaxis, independent predictors of ASNase-induced hypersensitivity reactions were found to be ASNase IC levels and ASNase-specific binding to leukocytes or basophils. Consistent with our multivariable analysis, we found that basophil depletion significantly protected mice from ASNase-induced hypersensitivity reactions, supporting that basophils are essential and can be used as a predictive marker of ASNase-induced anaphylaxis. Our study demonstrates the need for using tools that can detect both IC- and IgE-mediated hypersensitivity reactions to mitigate the risk of ASNase-induced hypersensitivity reactions during treatment.

Oxidative Stress and Chronic Myeloid Leukemia: A Balance between ROS-Mediated Pro- and Anti-Apoptotic Effects of Tyrosine Kinase Inhibitors.

The balanced reciprocal translocation t (9; 22) (q34; q11) and the BCR-ABL fusion gene, which produce p210 bcr-abl protein production with high tyrosine kinase activity, are characteristics of chronic myeloid leukemia, a myeloproliferative neoplasm. This aberrant protein affects several signaling pathways connected to both apoptosis and cell proliferation. It has been demonstrated that tyrosine kinase inhibitor treatment in chronic myeloid leukemia acts by inducing oxidative stress and, depending on its level, can activate signaling pathways responsible for either apoptosis or survival in leukemic cells. Additionally, oxidative stress and reactive oxygen species generation also mediate apoptosis through genomic activation. Furthermore, it was shown that oxidative stress has a role in both BCR-ABL-independent and BCR-ABL-dependent resistance pathways to tyrosine kinases, while patients with chronic myeloid leukemia were found to have a significantly reduced antioxidant level. The ideal environment for tyrosine kinase inhibitor therapy is produced by a favorable oxidative status. We discuss the latest studies that aim to manipulate the redox system to alter the apoptosis of cancerous cells.