Deciphering genetic and nongenetic factors underlying tumour dormancy: insights from multiomics analysis of two syngeneic MRD models of melanoma and leukemia.

BACKGROUND: Tumour dormancy, a resistance mechanism employed by cancer cells, is a significant challenge in cancer treatment, contributing to minimal residual disease (MRD) and potential relapse. Despite its clinical importance, the mechanisms underlying tumour dormancy and MRD remain unclear. In this study, we employed two syngeneic murine models of myeloid leukemia and melanoma to investigate the genetic, epigenetic, transcriptomic and protein signatures associated with tumour dormancy. We used a multiomics approach to elucidate the molecular mechanisms driving MRD and identify potential therapeutic targets. RESULTS: We conducted an in-depth omics analysis encompassing whole-exome sequencing (WES), copy number variation (CNV) analysis, chromatin immunoprecipitation followed by sequencing (ChIP-seq), transcriptome and proteome investigations. WES analysis revealed a modest overlap of gene mutations between melanoma and leukemia dormancy models, with a significant number of mutated genes found exclusively in dormant cells. These exclusive genetic signatures suggest selective pressure during MRD, potentially conferring resistance to the microenvironment or therapies. CNV, histone marks and transcriptomic gene expression signatures combined with Gene Ontology (GO) enrichment analysis highlighted the potential functional roles of the mutated genes, providing insights into the pathways associated with MRD. In addition, we compared "murine MRD genes" profiles to the corresponding human disease through public datasets and highlighted common features according to disease progression. Proteomic analysis combined with multi-omics genetic investigations, revealed a dysregulated proteins signature in dormant cells with minimal genetic mechanism involvement. Pathway enrichment analysis revealed the metabolic, differentiation and cytoskeletal remodeling processes involved in MRD. Finally, we identified 11 common proteins differentially expressed in dormant cells from both pathologies. CONCLUSIONS: Our study underscores the complexity of tumour dormancy, implicating both genetic and nongenetic factors. By comparing genomic, transcriptomic, proteomic, and epigenomic datasets, our study provides a comprehensive understanding of the molecular landscape of minimal residual disease. These results provide a robust foundation for forthcoming investigations and offer potential avenues for the advancement of targeted MRD therapies in leukemia and melanoma patients, emphasizing the importance of considering both genetic and nongenetic factors in treatment strategies.

HLA-DM and HLA-DO interplay for the peptide editing of HLA class II in healthy tissues and leukemia.

HLA class II antigen presentation is modulated by the activity of the peptide editor HLA-DM and its antagonist HLA-DO, with their interplay controlling the peptide repertoires presented by normal and malignant cells. The role of these molecules in allogeneic hematopoietic cell transplantation (alloHCT) is poorly investigated. Balanced expression of HLA-DM and HLA-DO can influence the presentation of leukemia-associated antigens and peptides targeted by alloreactive T cells, therefore affecting both anti-leukemia immunity and the potential onset of Graft versus Host Disease. We leveraged on a large collection of bulk and single cell RNA sequencing data, available at different repositories, to comprehensively review the level and distribution of HLA-DM and HLA-DO in different cell types and tissues of the human body. The resulting expression atlas will help future investigations aiming to dissect the dual role of HLA class II peptide editing in alloHCT, and their potential impact on its clinical outcome.

A potent and selective ENL degrader suppresses oncogenic gene expression and leukemia progression.

The histone acylation reader eleven-nineteen leukemia (ENL) plays a pivotal role in sustaining oncogenesis in acute leukemias, particularly in mixed-lineage leukemia-rearranged (MLL-r) leukemia. ENL relies on its reader domain to recognize histone lysine acylation promoting oncogenic gene expression and leukemia progression. Here, we report the development of MS41, a highly potent and selective von Hippel-Lindau-recruiting ENL degrader that effectively inhibits the growth of ENL-dependent leukemia cells. MS41-induced ENL degradation reduces the chromatin occupancy of ENL-associated transcription elongation machinery, resulting in the suppression of key oncogenic gene expression programs and the activation of differentiation genes. MS41 is well-tolerated in vivo and substantially suppresses leukemia progression in a xenograft mouse model of MLL-r leukemia. Notably, MS41 also induces the degradation of mutant ENL proteins identified in Wilms' tumors. Our findings emphasize the therapeutic potential of pharmacological ENL degradation for treating ENL-dependent cancers, making MS41 not only a valuable chemical probe but also potential anticancer therapeutic for further development.

Genetic analysis from multiple cohorts implies causality between 2200 druggable genes, telomere length, and leukemia.

BACKGROUND: Clinical therapeutic targets for leukemia remain to be identified and the causality between leukemia and telomere length is unclear. METHODS: This work employed cis expression quantitative trait locus (eQTL) for 2,200 druggable genes from the eQTLGen Consortium and genome-wide association studies (GWAS) summary data for telomere length in seven blood cell types from the UK Biobank, Netherlands Cohort as exposures. GWAS data for lymphoid leukemia (LL) and myeloid leukemia (ML) from FinnGen and Lee Lab were used as outcomes for discovery and replication cohorts, respectively. Robust Mendelian randomization (MR) findings were generated from seven MR models and a series of sensitivity analyses. Summary-data-based MR (SMR) analysis and transcriptome-wide association studies (TWAS) were further implemented to verify the association between identified druggable genes and leukemia. Single-cell type expression analysis was employed to identify the specific expression of leukemia casual genes on human bone marrow and peripheral blood immune cells. Multivariable MR analysis, linkage disequilibrium score regression (LDSC), and Bayesian colocalization analysis were performed to further validate the relationship between telomere length and leukemia. Mediation analysis was used to assess the effects of identified druggable genes affecting leukemia via telomere length. Phenome-wide MR (Phe-MR) analysis for assessing the effect of leukemia causal genes and telomere length on 1,403 disease phenotypes. RESULTS: Combining the results of the meta-analysis for MR estimates from two cohorts, SMR and TWAS analysis, we identified five LL causal genes (TYMP, DSTYK, PPIF, GDF15, FAM20A) and three ML causal genes (LY75, ADA, ABCA2) as promising drug targets for leukemia. Univariable MR analysis showed genetically predicted higher leukocyte telomere length increased the risk of LL (odds ratio [OR] = 2.33, 95 % confidence interval [95 % CI] 1.70-3.18; P = 1.33E-07), and there was no heterogeneity and horizontal pleiotropy. Evidence from the meta-analysis of two cohorts strengthened this finding (OR = 1.88, 95 % CI 1.06-3.05; P = 0.01). Multivariable MR analysis showed the causality between leukocyte telomere length and LL without interference from the other six blood cell telomere length (OR = 2.72, 95 % CI 1.88-3.93; P = 1.23E-07). Evidence from LDSC supported the positive genetic correlation between leukocyte telomere length and LL (rg = 0.309, P = 0.0001). Colocalization analysis revealed that the causality from leukocyte telomere length on LL was driven by the genetic variant rs770526 in the TERT region. The mediation analysis via two-step MR showed that the causal effect from TYMP on LL was partly mediated by leukocyte telomere length, with a mediated proportion of 12 %. CONCLUSION: Our study identified several druggable genes associated with leukemia risk and provided new insights into the etiology and drug development of leukemia. We also found that genetically predicted higher leukocyte telomere length increased LL risk and its potential mechanism of action.

Oncogenic Enhancers in Leukemia.

Although the study of leukemogenesis has traditionally focused on protein-coding genes, the role of enhancer dysregulation is becoming increasingly recognized. The advent of high-throughput sequencing, together with a better understanding of enhancer biology, has revealed how various genetic and epigenetic lesions produce oncogenic enhancers that drive transformation. These aberrations include translocations that lead to enhancer hijacking, point mutations that modulate enhancer activity, and copy number alterations that modify enhancer dosage. In this review, we describe these mechanisms in the context of leukemia and discuss potential therapeutic avenues to target these regulatory elements. Significance: Large-scale sequencing projects have uncovered recurrent gene mutations in leukemia, but the picture remains incomplete: some patients harbor no such aberrations, whereas others carry only a few that are insufficient to bring about transformation on their own. One of the missing pieces is enhancer dysfunction, which only recently has emerged as a critical driver of leukemogenesis. Knowledge of the various mechanisms of enhancer dysregulation is thus key for a complete understanding of leukemia and its causes, as well as the development of targeted therapies in the era of precision medicine.

KMT2A Rearrangements in Leukemias: Molecular Aspects and Therapeutic Perspectives.

KMT2A (alias: mixed-lineage leukemia [MLL]) gene mapping on chromosome 11q23 encodes the lysine-specific histone N-methyltransferase 2A and promotes transcription by inducing an open chromatin conformation. Numerous genomic breakpoints within the KMT2A gene have been reported in young children and adults with hematologic disorders and are present in up to 10% of acute leukemias. These rearrangements describe distinct features and worse prognosis depending on the fusion partner, characterized by chemotherapy resistance and high rates of relapse, with a progression-free survival of 30-40% and overall survival below 25%. Less intensive regimens are used in pediatric patients, while new combination therapies and targeted immunotherapeutic agents are being explored in adults. Beneficial therapeutic effects, and even cure, can be reached with hematopoietic stem cell transplantation, mainly in young children with dismal molecular lesions; however, delayed related toxicities represent a concern. Herein, we summarize the translocation partner genes and partial tandem duplications of the KMT2A gene, their molecular impact, clinical aspects, and novel targeted therapies.

[Aberrant Expression of Small Nucleolar RNA SNORA63 and Its Clinical Significance in Patients with Acute Leukemia].

OBJECTIVE: To investigate the expression level of small nucleolar RNA (snoRNA) SNORA63 in bone marrow of patients with acute leukemia (AL) and its significance in the clinical diagnosis, treatment and prognosis of AL patients. METHODS: Bone marrow samples of 53 newly diagnosed AL patients and 29 healthy subjects in the Affiliated Hospital of Guangdong Medical University from March 2018 to December 2021 were collected. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the relative expression level of SNORA63 in bone marrow mononuclear cells of the two groups. The median expression level of SNORA63 in AL patients was used as the boundary value to divide the patients into SNORA63 high and low expression groups, and the relationship between the expression level of SNORA63 and the clinical characteristics, clinical indicators and prognosis of AL patients was analyzed and discussed. RESULTS: The relative expression level of SNORA63 in AL patients was significantly lower than that in healthy control group [0.3018 (0.0244-1.2792) vs 1.0882 (0.2797-1.9889)] (P < 0.01). The expression level of SNORA63 in AL patients without remission after initial treatment was significantly lower than that in healthy controls and the patients who received complete remission (CR) (P < 0.01), while there was no statistical difference in the expression level of SNORA63 between AML and ALL groups (P >0.05). The abnormal low expression of SNORA63 was closely related to fever, hemorrage, poor prognosis, efficacy, platelets (PLT), lactate dehydrogenase (LDH), albumin (ALB), and molecular biological abnormalities of AL patients (P < 0.05), but not significantly correlated with sex, age, AL subtype, pallor, fatigue, extramedullary infiltration, white blood cell count (WBC), hemoglobin (HGB), C-reactive protein (CRP), procalcitonin (PCT), fibrinogen (FIB) or chromosome karyotype (P >0.05). Meanwhile, overall survival (OS) and event-free survival (EFS) of AL patients in SNORA63 high-expression group were significantly higher than those in SNORA63 low-expression group (P < 0.05). Univariate Cox regression analysis showed that SNORA63, molecular biological abnormalities, fever, PLT and LDH were the factors influencing OS and EFS in AL patients (P < 0.05). Multivariate Cox regression analysis indicated that fever, molecular biological abnormalities and LDH were independent factors associated with OS and EFS in AL patients (P < 0.05). CONCLUSION: SNORA63 is significantly down-expressed in AL patients, which is a molecular marker of great clinical value for disease monitoring and prognosis evaluation in AL patients.

Targeting the sulfur-containing amino acid pathway in leukemia.

sulfur-containing amino acids have been reported to patriciate in gene regulation, DNA methylation, protein synthesis and other physiological or pathological processes. In recent years, metabolism-related molecules of sulfur-containing amino acids affecting the occurrence, development and treatment of tumors have been implicated in various disorders, especially in leukemia. Here, we summarize current knowledge on the sulfur-containing amino acid metabolism pathway in leukemia and examine ongoing efforts to target this pathway, including treatment strategies targeting (a) sulfur-containing amino acids, (b) metabolites of sulfur-containing amino acids, and (c) enzymes and cofactors related to sulfur-containing amino acid metabolism in leukemia. Future leukemia therapy will likely involve innovative strategies targeting the sulfur-containing amino acid metabolism pathway.

Improving prediction of blood cancer using leukemia microarray gene data and Chi2 features with weighted convolutional neural network.

Blood cancer has emerged as a growing concern over the past decade, necessitating early diagnosis for timely and effective treatment. The present diagnostic method, which involves a battery of tests and medical experts, is costly and time-consuming. For this reason, it is crucial to establish an automated diagnostic system for accurate predictions. A particular field of focus in medical research is the use of machine learning and leukemia microarray gene data for blood cancer diagnosis. Even with a great deal of research, more improvements are needed to reach the appropriate levels of accuracy and efficacy. This work presents a supervised machine-learning algorithm for blood cancer prediction. This work makes use of the 22,283-gene leukemia microarray gene data. Chi-squared (Chi2) feature selection methods and the synthetic minority oversampling technique (SMOTE)-Tomek resampling is used to overcome issues with imbalanced and high-dimensional datasets. To balance the dataset for each target class, SMOTE-Tomek creates synthetic data, and Chi2 chooses the most important features to train the learning models from 22,283 genes. A novel weighted convolutional neural network (CNN) model is proposed for classification, utilizing the support of three separate CNN models. To determine the importance of the proposed approach, extensive experiments are carried out on the datasets, including a performance comparison with the most advanced techniques. Weighted CNN demonstrates superior performance over other models when coupled with SMOTE-Tomek and Chi2 techniques, achieving a remarkable 99.9% accuracy. Results from k-fold cross-validation further affirm the supremacy of the proposed model.

ETS1 Function in Leukemia and Lymphoma.

ETS proto-oncogene 1 (ETS1) is a transcription factor (TF) critically involved in lymphoid cell development and function. ETS1 expression is tightly regulated throughout differentiation and activation in T-cells, natural killer (NK) cells, and B-cells. It has also been described as an oncogene in a range of solid and hematologic cancer types. Among hematologic malignancies, its role has been best studied in T-cell acute lymphoblastic leukemia (T-ALL), adult T-cell leukemia/lymphoma (ATLL), and diffuse large B-cell lymphoma (DLBCL). Aberrant expression of ETS1 in these malignancies is driven primarily by chromosomal amplification and enhancer-driven transcriptional regulation, promoting the ETS1 transcriptional program. ETS1 also facilitates aberrantly expressed or activated transcriptional complexes to drive oncogenic pathways. Collectively, ETS1 functions to regulate cell growth, differentiation, signaling, response to stimuli, and viral interactions in these malignancies. A tumor suppressor role has also been indicated for ETS1 in select lymphoma types, emphasizing the importance of cellular context in ETS1 function. Research is ongoing to further characterize the clinical implications of ETS1 dysregulation in hematologic malignancies, to further resolve binding complexes and transcriptional targets, and to identify effective therapeutic targeting approaches.

HOXA9 Regulome and Pharmacological Interventions in Leukemia.

HOXA9, an important transcription factor (TF) in hematopoiesis, is aberrantly expressed in numerous cases of both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) and is a strong indicator of poor prognosis in patients. HOXA9 is a proto-oncogene which is both sufficient and necessary for leukemia transformation. HOXA9 expression in leukemia correlates with patient survival outcomes and response to therapy. Chromosomal transformations (such as NUP98-HOXA9), mutations, epigenetic dysregulation (e.g., MLL- MENIN -LEDGF complex or DOT1L/KMT4), transcription factors (such as USF1/USF2), and noncoding RNA (such as HOTTIP and HOTAIR) regulate HOXA9 mRNA and protein during leukemia. HOXA9 regulates survival, self-renewal, and progenitor cell cycle through several of its downstream target TFs including LMO2, antiapoptotic BCL2, SOX4, and receptor tyrosine kinase FLT3 and STAT5. This dynamic and multilayered HOXA9 regulome provides new therapeutic opportunities, including inhibitors targeting DOT1L/KMT4, MENIN, NPM1, and ENL proteins. Recent findings also suggest that HOXA9 maintains leukemia by actively repressing myeloid differentiation genes. This chapter summarizes the recent advances understanding biochemical mechanisms underlying HOXA9-mediated leukemogenesis, the clinical significance of its abnormal expression, and pharmacological approaches to treat HOXA9-driven leukemia.

Mechanistic insights into the developmental origin of pediatric hematologic disorders.

Embryonic and fetal hematopoietic stem and progenitor cells differ in some key properties from cells that are part of the adult hematopoietic system. These include higher proliferation and self-renewal capacity, different globin gene usage, and differing lineage biases. Although these evolved to cover specific requirements of embryonic development, they can have serious consequences for the pathogenesis of hematologic malignancies that initiate prebirth in fetal blood cells and may result in a particularly aggressive disease that does not respond well to treatments that have been designed for adult leukemias. This indicates that these infant/pediatric leukemias should be considered developmental diseases, where a thorough understanding of their unique biology is essential for designing more effective therapies. In this review, we will highlight some of these unique fetal properties and detail the underlying molecular drivers of these phenotypes. We specifically focus on those that are pertinent to disease pathogenesis and that may therefore reveal disease vulnerabilities. We have also included an extensive description of the origins, phenotypes, and key molecular drivers of the main infant and pediatric leukemias that have a known prenatal origin. Importantly, successes in recent years in generating faithful models of these malignancies in which cellular origins, key drivers, and potential vulnerabilities can be investigated have resulted in uncovering potential, new therapeutic avenues.

BOD1L mediates chromatin binding and non-canonical function of H3K4 methyltransferase SETD1A.

The H3K4 methyltransferase SETD1A plays an essential role in both development and cancer. However, essential components involved in SETD1A chromatin binding remain unclear. Here, we discovered that BOD1L exhibits the highest correlated SETD1A co-dependency in human cancer cell lines. BOD1L knockout reduces leukemia cells in vitro and in vivo, and mimics the transcriptional profiles observed in SETD1A knockout cells. The loss of BOD1L immediately reduced SETD1A distribution at transcriptional start sites (TSS), induced transcriptional elongation defect, and increased the RNA polymerase II content at TSS; however, it did not reduce H3K4me3. The Shg1 domain of BOD1L has a DNA binding ability, and a tryptophan residue (W104) in the domain recruits SETD1A to chromatin through the association with SETD1A FLOS domain. In addition, the BOD1L-SETD1A complex associates with transcriptional regulators, including E2Fs. These results reveal that BOD1L mediates chromatin and SETD1A, and regulates the non-canonical function of SETD1A in transcription.

Classic and molecular cytogenetic findings in leukemia patients from the Western part of Romania.

Acute lymphoblastic leukemia (ALL) is the most common type of leukemia in childhood and rare in adults, while acute myeloid leukemia (AML) is less common in children and more common in older adults. The aim of the study was to present our experience for the diagnostic of leukemia by using the classic and molecular cytogenetic methods. The study was conducted between 2009 and 2019 within the Classic and Molecular Genetic Laboratory of the Oncohematology Department from the Louis Turcanu Emergency Hospital for Children, Timisoara, Romania. The study group included 337 children and adults, evaluated between 2009 and 2019. By using the conventional and molecular cytogenetic technique, the cytogenetic anomalies found were 35 numerical chromosomal abnormalities, 10 (9;22)(q34;q11) [four ALL, one AML, five chronic myeloid leukemia (CML)] translocations, nine (15;17)(q24;q21) translocations, three (14;14)(q11;q32) translocations, two (4;11)(q21;q23) translocations, one (1;14)(p32;q11) translocation, one (7;14)(qter;q11) translocation, one (8;21)(q22;q22) translocation, one (9;14)(p12;q32) translocation, seven rearrangements of the MLL gene and two rearrangements of the core-binding factor subunit beta∕myosin heavy chain 11 (CBFB∕MYH11) gene. The use of conventional and molecular cytogenetic analysis is one of the most important prognostic indicators in acute leukemia patients, allowing the identification of biologically distinct subtypes of disease and selection of appropriate treatment approaches.

[Effect of donor and recipient HLA mismatched locus on the prognosis of childhood with leukemia after umbilical cord blood transplantation].

Objective: The aim of the study was to investigate the impact of the sites of high-resolution human leukocyte antigen (HLA) mismatch on the prognosis of children with leukemia undergoing umbilical cord blood transplantation (UCBT). Methods: Clinical data and high-resolution HLA-A, HLA-B, HLA-C, HLA-DRB1 and HLA-DQB1 locus gene information were collected in the children who underwent the UCBT for the first time at Children's Hospital of Soochow University between January 2016 and June 2023. In each locus, according to whether the two genes were compatible, they were divided into a compatible group (two genes were perfectly matched) and a non-compatible group (one gene was not matched). In different loci, the differences in occurrence, recurrence, non-recurrence death and survival of acute graft versus host disease (aGVHD) were compared between the two groups. Multivariate Cox regression was employed to analyzed the influencing factors for overall survival rate, and Fine-Gray proportional hazards model was employed to analyze the influencing factors of other outcome events. Results: A total of 100 patients were enrolled (55 males and 45 females), whose age [M (Q1, Q3)] at the time of transplantation was 3.9 (2.0, 6.5) years. There were 55 cases in the HLA-A matched group and 45 cases in the mismatched group. The 5-year non-recurrence mortality (NRM) in the HLA-A matched group was lower than that in the mismatched group (P=0.024). The cumulative incidence of aGVHD within 100 days after transplantation in the HLA-A matched group was lower than that in the mismatched group (P=0.017), and there were no statistically significant differences in other outcome events between the groups (all P>0.05). There were 70 cases in the HLA-B matched group and 30 cases in the mismatched group. The 5-year cumulative recurrence rate in the HLA-B matched group was higher than that in the mismatched group (P=0.027). There were 79 cases in the HLA-C matched group and 21 cases in the mismatched group, and there were no statistically difference in the outcome events between the groups (P>0.05). There were 73 cases in HLA-DRB1 matched group and 27 cases in mismatched group. The 5-year overall survival rate in HLA-DRB1 matched group was higher than that in mismatched group (P=0.036), the 5-year cumulative recurrence rate in HLA-DRB1 matched group was higher than that in mismatched group (P=0.028), and the 5-year NRM in HLA-DRB1 matched group was lower than that in mismatched group (P=0.008). The cumulative incidence of aGVHD within 100 days after transplantation in the matched group was lower than that in the mismatched group (P=0.010), and and there were no statistically significant difference in other outcome events between the groups (P>0.05). There were 68 cases in HLA-DQB1 matched group and 32 cases in mismatched group. There was no statistical difference in outcome events between the two groups (all P>0.05). The risk of aGVHD in HLA-A mismatched group was higher than that in HLA-A matched group (HR=1.25, 95%CI: 1.12-1.38). The risk of recurrence in HLA-B mismatched group was lower than that in HLA-B matched group (HR=0.77, 95%CI: 0.63-0.91). Mismatched group at HLA-DRB1 compared with matched group at HLA-DRB1, had a higher risk of aGVHD (HR=1.37, 95%CI: 1.26-1.48), a higher risk of non-recurrence death (HR=1.39, 95%CI: 1.28-1.50), and a higher risk of death (HR=1.27, 95%CI: 1.18-1.36). No association was found between HLA-C and HLA-DQB1 locus with the risk of aGVHD, recurrence, non-recurrence death, and survival (all P>0.05). Conclusions: In UCBT, the risk of aGVHD in children with matching HLA-A sites of donor and recipient is lower than that in children with incompatible HLA-A sites. Compared with children with incompatible HLA-DRB1 sites, children with HLA-DRB1 matched sites has a lower risk of acute GVHD, a lower 5-year NRM, and a higher risk of death. The recurrence rate of children with matching HLA-B loci is higher than that of children without matching HLA-B loci.

Exploring the causal relationship between glutamine metabolism and leukemia risk: a Mendelian randomization and LC-MS/MS analysis.

Objective: This investigation sought to delineate the causal nexus between plasma glutamine concentrations and leukemia susceptibility utilizing bidirectional Mendelian Randomization (MR) analysis and to elucidate the metabolic ramifications of asparaginase therapy on glutamine dynamics in leukemia patients. Methods: A bidirectional two-sample MR framework was implemented, leveraging genetic variants as instrumental variables from extensive genome-wide association studies (GWAS) tailored to populations of European descent. Glutamine quantification was executed through a rigorously validated Liquid Chromatography-Mass Spectrometry/Mass Spectrometry (LC-MS/MS) protocol. Comparative analyses of glutamine levels were conducted across leukemia patients versus healthy controls, pre- and post-asparaginase administration. Statistical evaluations employed inverse variance weighted (IVW) models, MR-Egger regression, and sensitivity tests addressing pleiotropy and heterogeneity. Results: The MR findings underscored a significant inverse association between glutamine levels and leukemia risk (IVW p = 0.03558833), positing lower glutamine levels as a contributory factor to heightened leukemia susceptibility. Conversely, the analysis disclosed no substantive causal impact of leukemia on glutamine modulation (IVW p = 0.9694758). Notably, post-asparaginase treatment, a marked decrement in plasma glutamine concentrations was observed in patients (p = 0.0068), underlining the profound metabolic influence of the therapeutic regimen. Conclusion: This study corroborates the hypothesized inverse relationship between plasma glutamine levels and leukemia risk, enhancing our understanding of glutamine's role in leukemia pathophysiology. The pronounced reduction in glutamine levels following asparaginase intervention highlights the critical need for meticulous metabolic monitoring to refine therapeutic efficacy and optimize patient management in clinical oncology. These insights pave the way for more tailored and efficacious treatment modalities in the realm of personalized medicine.

Ubiquitin-specific proteases (USPs) in leukemia: a systematic review.

BACKGROUND: Leukemia, a type of blood cell cancer, is categorized by the type of white blood cells affected (lymphocytes or myeloid cells) and disease progression (acute or chronic). In 2020, it ranked 15th among the most diagnosed cancers and 11th in cancer-related deaths globally, with 474,519 new cases and 311,594 deaths (GLOBOCAN2020). Research into leukemia's development mechanisms may lead to new treatments. Ubiquitin-specific proteases (USPs), a family of deubiquitinating enzymes, play critical roles in various biological processes, with both tumor-suppressive and oncogenic functions, though a comprehensive understanding is still needed. AIM: This systematic review aimed to provide a comprehensive review of how Ubiquitin-specific proteases are involved in pathogenesis of different types of leukemia. METHODS: We systematically searched the MEDLINE (via PubMed), Scopus, and Web of Science databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA) to identify relevant studies focusing on the role of USPs in leukemia. Data from selected articles were extracted, synthesized, and organized to present a coherent overview of the subject matter. RESULTS: The review highlights the crucial roles of USPs in chromosomal aberrations, cell proliferation, differentiation, apoptosis, cell cycle regulation, DNA repair, and drug resistance. USP activity significantly impacts leukemia progression, inhibition, and chemotherapy sensitivity, suggesting personalized diagnostic and therapeutic approaches. Ubiquitin-specific proteases also regulate gene expression, protein stability, complex formation, histone deubiquitination, and protein repositioning in specific leukemia cell types. CONCLUSION: The diagnostic, prognostic, and therapeutic implications associated with ubiquitin-specific proteases (USPs) hold significant promise and the potential to transform leukemia management, ultimately improving patient outcomes.

The RNA helicases DDX19A/B modulate selinexor sensitivity by regulating MCL1 mRNA nuclear export in leukemia cells.

Selinexor, a first-in-class exportin1 (XPO1) inhibitor, is an attractive anti-tumor agent because of its unique mechanisms of action; however, its dose-dependent toxicity and lack of biomarkers preclude its wide use in clinical applications. To identify key molecules/pathways regulating selinexor sensitivity, we performed genome-wide CRISPR/Cas9 dropout screens using two B-ALL lines. We identified, for the first time, that paralogous DDX19A and DDX19B RNA helicases modulate selinexor sensitivity by regulating MCL1 mRNA nuclear export. While single depletion of either DDX19A or DDX19B barely altered MCL1 protein levels, depletion of both significantly attenuated MCL1 mRNA nuclear export, reducing MCL1 protein levels. Importantly, combining selinexor treatment with depletion of either DDX19A or DDX19B markedly induced intrinsic apoptosis of leukemia cells, an effect rescued by MCL1 overexpression. Analysis of Depmap datasets indicated that a subset of T-ALL lines expresses minimal DDX19B mRNA levels. Moreover, we found that either selinexor treatment or DDX19A depletion effectively induced apoptosis of T-ALL lines expressing low DDX19B levels. We conclude that XPO1 and DDX19A/B coordinately regulate cellular MCL1 levels and propose that DDX19A/B could serve as biomarkers for selinexor treatment. Moreover, pharmacological targeting of DDX19 paralogs may represent a potential strategy to induce intrinsic apoptosis in leukemia cells.

hnRNPA0 promotes MYB expression by interacting with enhancer lncRNA MY34UE-AS in human leukemia cells.

MYB is a key regulator of hematopoiesis and erythropoiesis, and dysregulation of MYB is closely involved in the development of leukemia, however the mechanism of MYB regulation remains still unclear so far. Our previous study identified a long noncoding RNA (lncRNA) derived from the -34 kb enhancer of the MYB locus, which can promote MYB expression, the proliferation and migration of human leukemia cells, and is therefore termed MY34UE-AS. Then the interacting partner proteins of MY34UE-AS were identified and studied in the present study. hnRNPA0 was identified as a binding partner of MY34UE-AS through RNA pulldown assay, which was further validated through RNA immunoprecipitation (RIP). hnRNPA0 interacted with MY34UE-AS mainly through its RRM2 domain. hnRNPA0 overexpression upregulated MYB and increased the proliferation and migration of K562 cells, whereas hnRNPA0 knockdown showed opposite effects. Rescue experiments showed MY34UE-AS was required for above mentioned functions of hnRNPA0. These results reveal that hnRNPA0 is involved in leukemia through upregulating MYB expression by interacting with MY34UE-AS, suggesting that the hnRNPA0/MY34UE-AS axis could serve as a potential target for leukemia treatment.