Leukemia Gene Research Articles

JMJD1C forms condensates to facilitate a RUNX1-dependent gene expression program shared by multiple types of AML cells.

JMJD1C, a member of the lysine demethylase 3 (KDM3) family, is universally required for the survival of several types of acute myeloid leukemia (AML) cells with different genetic mutations, representing a therapeutic opportunity with broad application. Yet how JMJD1C regulates the leukemic programs of various AML cells is largely unexplored. Here we show that JMJD1C interacts with the master hematopoietic transcription factor RUNX1, which thereby recruits JMJD1C to the genome to facilitate a RUNX1-driven transcriptional program that supports leukemic cell survival. The underlying mechanism hinges on the long N-terminal disordered region of JMJD1C, which harbors two inseparable abilities: condensate formation and direct interaction with RUNX1. This dual capability of JMJD1C may influence enhancer-promoter contacts crucial for the expression of key leukemic genes regulated by RUNX1. Our findings demonstrate a previously unappreciated role for the non-catalytic function of JMJD1C in transcriptional regulation, underlying a mechanism shared by different types of leukemias.

NPM1-fusion proteins promote myeloid leukemogenesis through XPO1-dependent HOX activation.

Nucleophosmin (NPM1) is a nucleolar protein and one of the most frequently mutated genes in acute myeloid leukemia (AML). In addition to the commonly detected frameshift mutations in exon12 (NPM1c), previous studies have identified NPM1 gene rearrangements leading to the expression of NPM1-fusion proteins in pediatric AML. However, whether the NPM1-fusions are indeed oncogenic and how the NPM1-fusions cause AML have been largely unknown. In this study, we investigated the subcellular localization and leukemogenic potential of two rare NPM1-fusion proteins, NPM1::MLF1 and NPM1::CCDC28A. NPM1::MLF1 is present in both the nucleus and cytoplasm and occasionally induces AML in the mouse transplantation assay. NPM1::CCDC28A is more localized to the cytoplasm, immortalizes mouse bone marrow cells in vitro and efficiently induces AML in vivo. Mechanistically, both NPM1-fusions bind to the HOX gene cluster and, like NPM1c, cause aberrant upregulation of HOX genes in cooperation with XPO1. The XPO1 inhibitor selinexor suppressed HOX activation and colony formation driven by the NPM1-fusions. NPM1::CCDC28A cells were also sensitive to menin inhibition. Thus, our study provides experimental evidence that both NPM1::MLF1 and NPM1::CCDC28A are oncogenes with functions similar to NPM1c. Inhibition of XPO1 and menin may be a promising strategy for the NPM1-rearranged AML.

Budget impact analysis of TPMT and NUDT15 pharmacogenomic testing for 6-mercaptopurine in pediatric acute lymphoblastic leukemia patients.

Pharmacogenomic testing identifies gene polymorphisms impacting drug metabolism, aiding in optimizing treatment efficacy and minimizing toxicity, thus potentially reducing healthcare utilization. 6-Mercaptopurine metabolism is affected by thiopurine methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15) polymorphisms. We sought to estimate the budget impact of preemptive pharmacogenomic testing for these genes in pediatric acute lymphoblastic leukemia (ALL) patients from an institutional perspective. A Markov model was constructed to model the first cycle of the maintenance phase of chemotherapy for pediatric ALL patients transitioning between one of three health states: stable, moderately myelosuppressed, and severely myelosuppressed over 16 weeks, with each health state's associated costs derived from the literature. The patient's likelihood to experience moderate or severe myelosuppression based on metabolism phenotype was calculated from the literature and applied on a weekly basis, and the marginal budget impact of preemptive pharmacogenomic testing vs. no pharmacogenomic testing was calculated. One-way sensitivity analysis was conducted to assess parameter influence on results. Preemptive pharmacogenomic testing of TPMT and NUDT15 provided savings of up to $26 028 per patient during the maintenance phase. In the sensitivity analysis, the cost of outpatient management of moderate myelosuppression had the greatest impact on the budget, resulting in cost savings ranging from $8592 to $30 129 when the minimum and maximum costs of management were used in the model. Preemptive pharmacogenomic testing for TPMT and NUDT15 polymorphisms before initiation of maintenance therapy for pediatric ALL patients yielded considerable cost savings.

The enigma of KMT2A gene in hematological disorders

Abstract Introduction/Objective Presence of distinct MLL rearrangements is an independent dismal prognostic factor. Rearrangements of the histone lysine [K]- MethylTransferase 2A gene (KMT2A) on chromosome 11q23, formerly known as the mixed-lineage leukemia (MLL) gene, are found in 10% and 5% of adult and children with acute leukemia respectively. Chromosome 11 breakpoints are typically localized to band 11q23.3, frequently altering the proto- oncogene KMT2A/MLL whereas partner chromosomes involved in translocation may vary. More than 80 different gene partners involved in this fusion have been described, although the majority of leukemias results from 6 common partner genes. KMT2A gene rearrangement are associated with poor prognosis in both Lymphoid and Myeloid leukemia. Methods/Case Report A retrospective study conducted in Cytogenetic laboratory of The Indus hospital, Karachi. All karyotype cases (age 1-60 year) with chromosome 11 aberrations were included from October 2020 to December 2022. Karyotype and FISH performed using G-banding and break a part probe for MLL respectively. Results (if a Case Study enter NA) Total of 923 cases received for karyotyping out of which 32(3.4%) cases were reported for 11q23 abnormalities. The median age was 5 (1.25-12.5) years, majority 15 (47%) were 1-10 years, 9(28%) were >10 years and 7(22%) were <1 years. M:F ratio was 1.9:1. B-ALL were 19(59.4%), AML 8(25%), and 5 (15.6%) were others. FISH performed in 23(72%) cases, 21 (91%) showed concordance with karyotype. The t(9;11) was the commonest 7(22%), followed by t(4;11) and (1;11). Chromosome 9 was the most common partner identified in B-ALL. Loss of 11q23 observed in 3 (13%) cases. Conclusion The findings underscore the heterogeneity of partner chromosomes involved in KMT2A gene rearrangements and emphasize the importance of employing both FISH and karyotyping for comprehensive detection. The high concordance rate between the two methods supports their complementary roles in clinical diagnostics. Understanding the specific translocations and partner chromosomes associated with MLL gene rearrangements contributes valuable insights for prognostication and targeted therapeutic strategies in acute leukemia. FISH and karyotype showed 91% concordance to detect this aberration.

Expression Analysis of Caspase-3 (CASP3) Gene in Leukemia Patients Using Quantitative Polymerase Chain Reaction (qPCR) and Western Blot Techniques

CASP3 belongs to the caspases family and accounts for several critical activities, including apoptosis and other pathological and physiological processes. CASP3 also influences the multiple functions in cellular development such as homeostasis, hematopoietic growth and embryonic growth. It has significant involvement in the initiation and development of cancers including breast, colon and uterine cancers. However, molecular studies on the CASP3 gene in leukemia have not been widely conducted. The present study was designed to analyse the expression level of the CASP3 gene in leukemia patients. The results were further compared between different parameters such as types of leukemia, age, gender, occupation, WBC count and location-based. About 112 leukemia blood samples along adjacent controls were collected to analyse the CASP3 expression in this study cohort. The mRNA of each patient and control samples were isolated, quantified and converted to complementary DNA (cDNA). Relative expression of the CASP3 gene was measured using the quantitative PCR (qPCR) and Western blot analyses. Results showed that the relative expression of CASP3 was found to be significantly downregulated at both mRNA and protein levels in leukemia patients compared to normal controls. Further analysis showed that expression of CASP3 was downregulated in patients receiving the combination of chemotherapy as well as radiotherapy compared with patients receiving chemotherapy. These findings from our research showed the lower expression of CASP3 is associated with an increased risk of development and proliferation of leukemia. It can, therefore, be concluded that lower expression of the CASP3 gene may contribute to the initiation and development of leukemia.

Prognostic implications of metabolism-related genes in acute myeloid leukemia.

Acute myeloid leukemia(AML) is a diverse malignancy with a prognosis that varies, being especially unfavorable in older patients and those with high-risk characteristics. Metabolic reprogramming has become a significant factor in AML development , presenting new opportunities for prognostic assessment and therapeutic intervention. Metabolism-related differentially expressed genes (mDEGs) were identified by integrating KEGG metabolic gene lists with AML gene expression data from GSE63270. Using TCGA data, we performed consensus clustering and survival analysis to investigate the prognostic significance of mDEGs. A metabolic risk model was constructed using LASSO Cox reg ression and enhanced by a nomogram incorporated clinical characteristics. The model was validated through receiver operating characteristic (ROC) curves and survival statistics. Gene network analysis was conducted to identify critical prognostic factors. The tumor immune microenvironment was evaluated using CIBERSORT and ESTIMATE algorithms, followed by correlation analysis between immune checkpoint gene expression and risk scores. Drug sensitivity predictions and in vitro assays were performed to explore the effects of mDEGs on cell proliferation and chemoresistance. An 11-gene metabolic prognostic model was established and validated. High-risk patients had worse overall survival in both training and validation cohorts (p < 0.05). The risk score was an independent prognostic factor. High-risk patients showed increased immune cell infiltration and potential response to checkpoint inhibitors but decreased drug sensitivity. The model correlated with sensitivity to drugs such as venetoclax. Carbonic anhydrase 13 (CA13) was identified as a key gene related to prognosis and doxorubicin resistance. Knocking down CA13 reduced proliferation and increased cell death with doxorubicin treatment. A novel metabolic gene signature was developed to stratify risk and predict prognosis in AML, serving as an independent prognostic factor. CA13 was identified as a potential therapeutic target. This study provides new insights into the prognostic and therapeutic implications of metabolic genes in AML.

A review on the functional characteristics of the c-Myeloproliferative Leukaemia (c-MPL) gene and its isoforms.

The c-MPL-TPO axis regulates hematopoiesis by activating various signalling cascades, including JAK/STAT, MAPK/ERK, and PIK3/AKT. Here, we have summarized how TPO is regulated by c-MPL and, how mutations in the c-MPL regulate hematopoiesis. We also focus on its non-hematological regulatory role in diseases like Unstable Angina and pathways like DNA damage repair, skeletal homeostasis, & apoptotic regulation of neurons/HSCs at the embryonic state. We discuss the therapeutic efficiency of c-MPL and, its potential to be developed as a bio-marker for detecting metastasis and development of chemo-resistance in various cancers, justifying the multifaceted nature of c-MPL. We have also highlighted the importance of c-MPL isoforms and their stoichiometry in controlling the HSC quiescent and proliferative state. The regulation of the ratio of different isoforms through gene-therapy can open future therapeutic avenues. A systematic understanding of c-MPL-isoforms would undoubtedly take one step closer to facilitating c-MPL from basic-research towards translational medicine.

Improving data interpretability with new differential sample variance gene set tests.

Gene set analysis methods have played a major role in generating biological interpretations from omics data such as gene expression datasets. However, most methods focus on detecting homogenous pattern changes in mean expression and methods detecting pattern changes in variance remain poorly explored. While a few studies attempted to use gene-level variance analysis, such approach remains under-utilized. When comparing two phenotypes, gene sets with distinct changes in subgroups under one phenotype are overlooked by available methods although they reflect meaningful biological differences between two phenotypes. Multivariate sample-level variance analysis methods are needed to detect such pattern changes. We use ranking schemes based on minimum spanning tree to generalize the Cramer-Von Mises and Anderson-Darling univariate statistics into multivariate gene set analysis methods to detect differential sample variance or mean. We characterize these methods in addition to two methods developed earlier using simulation results with different parameters. We apply the developed methods to microarray gene expression dataset of prednisolone-resistant and prednisolone-sensitive children diagnosed with B-lineage acute lymphoblastic leukemia and bulk RNA-sequencing gene expression dataset of benign hyperplastic polyps and potentially malignant sessile serrated adenoma/polyps. One or both of the two compared phenotypes in each of these datasets have distinct molecular subtypes that contribute to heterogeneous differences. Our results show that methods designed to detect differential sample variance are able to detect specific hallmark signaling pathways associated with the two compared phenotypes as documented in available literature. The results in this study demonstrate the usefulness of methods designed to detect differential sample variance in providing biological interpretations when biologically relevant but heterogeneous changes between two phenotypes are prevalent in specific signaling pathways. Software implementation of the developed methods is available with detailed documentation from Bioconductor package GSAR. The available methods are applicable to gene expression datasets in a normalized matrix form and could be used with other omics datasets in a normalized matrix form with available collection of feature sets.

Developments of Fms-like Tyrosine Kinase 3 Inhibitors as Anticancer Agents for AML Treatment.

FMS-like tyrosine kinase 3 (FLT3) is a commonly mutated gene in acute myeloid leukemia. As a receptor tyrosine kinase (RTK), FLT3 plays a role in the proliferation and differentiation of hematopoietic stem cells. As the most frequent molecular alteration in AML, FLT3 has drawn the attention of many researchers, and a lot of small molecule inhibitors targeting FLT3 have been intensively investigated as potential drugs for AML therapy. In this paper, PubMed and SciFinder® were used as a tool; the publications about "FLT3 inhibitor" and "Acute myeloid leukemia" were surveyed from 2014 to the present with an exclusion of those published as patents. In this study, the structural characterization and biological activities of representative FLT3 inhibitors were summarized. The major challenges and future directions for further research are discussed. Recently, numerous FLT3 inhibitors have been discovered and employed in FLT3-mutated AML treatment. In order to overcome the drug resistance caused by FLT3 mutations, screening multitargets FLT3 inhibitors has become the main research direction. In addition, the emergence of irreversible FLT3 inhibitors also provides new ideas for discovering new FLT3 inhibitors.

835P Genetic, epigenetic, and clinical significance of Wilms’ tumor 1 (WT1) gene in acute myeloid leukemia

835P Genetic, epigenetic, and clinical significance of Wilms’ tumor 1 (WT1) gene in acute myeloid leukemia

836P A prospective study to evaluate the prognostic implications and molecular mechanism of SLC40A1 gene in primary acute myeloid leukemia

836P A prospective study to evaluate the prognostic implications and molecular mechanism of SLC40A1 gene in primary acute myeloid leukemia

Dexamethasone Inhibits the Growth of B-Lymphoma Cells by Downregulating DOT1L.

Dexamethasone (Dex), a synthetic glucocorticoid that acts by binding to the glucocorticoid receptor (GR), has been widely applied to treat leukemia and lymphoma; however, the precise mechanism underlying Dex action is still not well elucidated. DOT1L, a histone H3-lysine79 (H3K79) methyltransferase, has been linked to multiple cancer types, particularly mixed lineage leukemia (MLL) gene rearranged leukemia, but its contribution to lymphoma is yet to be delineated. Analysis from the TCGA database displayed that DOT1L was highly expressed in lymphoma and leukemia. We initially demonstrated that DOT1L served as a new target gene controlled by GR, and the downregulation of DOT1L was critical for the killing of B-lymphoma cells by Dex. Further study revealed that Dex had no impact on the transcriptional activity of the DOT1L promoter, rather it reduced the mRNA level of DOT1L at the posttranscriptional level. In addition, knockdown of DOT1L remarkably inhibited the B-lymphoma cell growth. Overall, our findings indicated that DOT1L may serve as a potential drug target and a promising biomarker of Dex sensitivity when it comes to treating B lymphoma.

Biallelic Loss of Certain Genes in Adult Ph-Negative T-Acute Lymphoblastic Leukemia

Biallelic Loss of Certain Genes in Adult Ph-Negative T-Acute Lymphoblastic Leukemia

A Prospective Study to Evaluate the Prognostic Implications and Molecular Mechanism of SLC40A1 Gene in Primary Acute Myeloid Leukemia

A Prospective Study to Evaluate the Prognostic Implications and Molecular Mechanism of SLC40A1 Gene in Primary Acute Myeloid Leukemia

Genetic, Epigenetic, and Clinical Significance of Wilms’ Tumor 1 (WT-1) Gene in Acute Myeloid Leukemia

Genetic, Epigenetic, and Clinical Significance of Wilms’ Tumor 1 (WT-1) Gene in Acute Myeloid Leukemia

ALL-480 Biallelic Loss of Certain Genes in Adult Ph-Negative T-Acute Lymphoblastic Leukemia

ALL-480 Biallelic Loss of Certain Genes in Adult Ph-Negative T-Acute Lymphoblastic Leukemia

AML-016 Genetic, Epigenetic, and Clinical Significance of Wilms’ Tumor 1 (WT-1) Gene in Acute Myeloid Leukemia

AML-016 Genetic, Epigenetic, and Clinical Significance of Wilms’ Tumor 1 (WT-1) Gene in Acute Myeloid Leukemia

The Dichotomous Role of Ten-Eleven Translocation (TET1) 1 Gene in Acute Lymphoblastic Leukemia

The Dichotomous Role of Ten-Eleven Translocation (TET1) 1 Gene in Acute Lymphoblastic Leukemia

AML-013 A Prospective Study to Evaluate the Prognostic Implications and Molecular Mechanism of SLC40A1 Gene in Primary Acute Myeloid Leukemia

AML-013 A Prospective Study to Evaluate the Prognostic Implications and Molecular Mechanism of SLC40A1 Gene in Primary Acute Myeloid Leukemia

Impact of Age on Pharmacogenomics and Treatment Outcomes of B-Cell Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL) can occur across all age groups, with a strikingly higher cure rate in children compared with adults. However, the pharmacological basis of age-related differences in ALL treatment response remains unclear. Studying 767 children and 309 adults with newly diagnosed B-cell ALL enrolled on frontline trials at St Jude Children's Research Hospital, MD Anderson Cancer Center, the Alliance for Clinical Trials in Oncology, and the ECOG-ACRIN Cancer Research Group, we determined the ex vivo sensitivity of leukemia cells to 21 drugs. Twenty-three ALL molecular subtypes were identified using RNA sequencing. We systematically characterized the associations between drug response and ALL genomics in children, adolescents and young adults, and elderly adults. We evaluated the effect of age-related gene expression signature on ALL treatment outcomes. Seven ALL drugs (asparaginase, prednisolone, mercaptopurine, dasatinib, nelarabine, daunorubicin, and inotuzumab ozogamicin) showed differential activity between children and adults, of which six were explained by age-related differences in leukemia molecular subtypes. Adolescents and young adults showed similar patterns of drug resistance as older adults, relative to young children. Mercaptopurine exhibited subtype-independent greater sensitivity in children. Transcriptomic profiling uncovered subclusters within CRLF2-, DUX4-, and KMT2A-rearranged ALL that were linked to age and cytotoxic drug resistance. In particular, a subset of children had adult-like ALL on the basis of leukemia gene expression patterns across subtypes, despite their chronological age. Resistant to cytotoxic drugs, children with adult-like ALL exhibited poor prognosis in pediatric ALL trials, even after adjusting for age and minimal residual diseases. Our results provide pharmacogenomic insights into age-related disparities in ALL cure rates and identify leukemia prognostic features for treatment individualization across age groups.