ORCID Profile
0000-0002-9023-0138
Current Organisations
University of South Australia
,
SA Pathology
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Publisher: Springer Science and Business Media LLC
Date: 29-03-2019
Publisher: American Society of Hematology
Date: 02-07-2020
Abstract: Recognition that germline mutations can predispose in iduals to blood cancers, often presenting as secondary leukemias, has largely been driven in the last 20 years by studies of families with inherited mutations in the myeloid transcription factors (TFs) RUNX1, GATA2, and CEBPA. As a result, in 2016, classification of myeloid neoplasms with germline predisposition for each of these and other genes was added to the World Health Organization guidelines. The incidence of germline mutation carriers in the general population or in various clinically presenting patient groups remains poorly defined for reasons including that somatic mutations in these genes are common in blood cancers, and our ability to distinguish germline (inherited or de novo) and somatic mutations is often limited by the laboratory analyses. Knowledge of the regulation of these TFs and their mutant alleles, their interaction with other genes and proteins and the environment, and how these alter the clinical presentation of patients and their leukemias is also incomplete. Outstanding questions that remain for patients with these germline mutations or their treating clinicians include: What is the natural course of the disease? What other symptoms may I develop and when? Can you predict them? Can I prevent them? and What is the best treatment? The resolution of many of the remaining clinical and biological questions and effective evidence-based treatment of patients with these inherited mutations will depend on worldwide partnerships among patients, clinicians, diagnosticians, and researchers to aggregate sufficient longitudinal clinical and laboratory data and integrate these data with model systems.
Publisher: Springer Science and Business Media LLC
Date: 28-11-2012
DOI: 10.1038/LEU.2012.346
Publisher: Wiley
Date: 12-2013
DOI: 10.1002/IUB.1233
Abstract: The mechanisms by which cells control their growth and behavioral identities are complex and require adaptability to environmental changes. Transcription factors act as master controllers of many of these pivotal points through their ability to influence the expression of many thousands of downstream genes, and increasingly research is showing that transcription factor regulation of target genes can change in response to environmental stimuli and cell type such that their function is not prescribed but rather context-dependent. Krüppel like factor 5 (KLF5) is an ex le of such a transcription factor, where evidence of disparate effects on cell growth and differentiation in normal and transformed tissue are clear. Here we present and discuss the literature covering the differential roles of KLF5 in particular tissues and cancer states, and the mechanisms by which these differences are effected through the regulation of KLF5 protein function in response to different cellular states and the direct effect on target gene expression.
Publisher: American Association for Cancer Research (AACR)
Date: 30-08-2012
DOI: 10.1158/0008-5472.CAN-12-1832
Abstract: Patients diagnosed with leukemia approach their treatment with the hope of cure despite the effect on their quality of life. Some patients will be cured, others will die from treatment, and some will die of their disease. A common theme at the New Directions in Leukemia Research (NDLR 2012) meeting was that cure will come if the drivers of the disease are better understood. Key messages included the power of combination platforms to understand the genetic and epigenetic modifications in leukemia to enable development of rational therapies, which can be tested via new clinical trial designs ensuring rapid clinical implementation. Cancer Res 72(17) 4300–3. ©2012 AACR.
Publisher: American Society of Hematology
Date: 15-01-2004
DOI: 10.1182/BLOOD-2003-05-1435
Abstract: Activation of the granulocyte-macrophage colony-stimulating factor (GM-CSF) family of receptors promotes the survival, proliferation, and differentiation of cells of the myeloid compartment. Several signaling pathways are activated downstream of the receptor, however it is not clear how these induce specific biologic outcomes. We have previously identified 2 classes of constitutively active mutants of the shared signaling subunit, human (h) βc, of the human GM-CSF/interleukin-3 (IL-3)/IL-5 receptors that exhibit different modes of signaling. In a factor-dependent bipotential myeloid cell line, FDB1, an activated mutant containing a substitution in the transmembrane domain (V449E) induces factor-independent proliferation and survival, while mutants in the extracellular domain induce factor-independent granulocyte-macrophage differentiation. Here we have used further mutational analysis to demonstrate that there are nonredundant functions for several regions of the cytoplasmic domain with regard to mediating proliferation, viability, and differentiation, which have not been revealed by previous studies with the wild-type GM-CSF receptor. This unique lack of redundancy has revealed an association of a conserved membrane-proximal region with viability signaling and a critical but distinct role for tyrosine 577 in the activities of each class of mutant.
Publisher: American Society of Hematology
Date: 30-03-2023
Abstract: Hereditary platelet disorders (HPDs) are a group of blood disorders with variable severity and clinical impact. Although phenotypically there is much overlap, known genetic causes are many, prompting the curation of multigene panels for clinical use, which are being deployed in increasingly large-scale populations to uncover missing heritability more efficiently. For some of these disorders, in particular RUNX1, ETV6, and ANKRD26, pathogenic germ line variants in these genes also come with a risk of developing hematological malignancy (HM). Although they may initially present as similarly mild-moderate thrombocytopenia, each of these 3 disorders have distinct penetrance of HM and a different range of somatic alterations associated with malignancy development. As our ability to diagnose HPDs has improved, we are now faced with the challenges of integrating these advances into routine clinical practice for patients and how to optimize management and surveillance of patients and carriers who have not developed malignancy. The volume of genetic information now being generated has created new challenges in how to accurately assess and report identified variants. The answers to all these questions involve international initiatives on rare diseases to better understand the biology of these disorders and design appropriate models and therapies for preclinical testing and clinical trials. Partnered with this are continued technological developments, including the rapid sharing of genetic variant information and automated integration with variant classification relevant data, such as high-throughput functional data. Collective progress in this area will drive timely diagnosis and, in time, leukemia preventive therapeutic interventions.
Publisher: Elsevier BV
Date: 04-2017
Publisher: Elsevier BV
Date: 04-2017
DOI: 10.1053/J.SEMINHEMATOL.2016.11.003
Abstract: Hereditary hematologic malignancy (HM) syndromes are increasingly recognized as causative of adult hematopoietic cancers, and the advent of next-generation sequencing has accelerated the discovery of new syndromes based on dense clustering of these diseases in particular families. Updated classifications schemes for myeloid malignancies will now include recommendations for taking a family history on all patients diagnosed with hematopoietic malignancies and for genetic counseling and testing of appropriate in iduals and families. Therefore, now more than ever, clinicians and pathologists will need to have a high index of suspicion and be familiar with the aspects of a patient's personal or family history that should raise suspicion regarding these syndromes as well as the options for clinical testing. Whenever possible, in iduals should be tested with certified, clinical platforms that can detect both point mutations and genomic rearrangements that disrupt gene function so that results are immediately actionable. In iduals and families who test negative for mutations in the known germline predisposition genes serve as important sources of discovery for new inherited susceptibility syndromes.
Publisher: Springer Science and Business Media LLC
Date: 04-2013
DOI: 10.1186/1471-2105-14-S5-S10
Abstract: DNA methylation profiling reveals important differentially methylated regions (DMRs) of the genome that are altered during development or that are perturbed by disease. To date, few programs exist for regional analysis of enriched or whole-genome bisulfate conversion sequencing data, even though such data are increasingly common. Here, we describe an open-source, optimized method for determining empirically based DMRs (eDMR) from high-throughput sequence data that is applicable to enriched whole-genome methylation profiling datasets, as well as other globally enriched epigenetic modification data. Here we show that our bimodal distribution model and weighted cost function for optimized regional methylation analysis provides accurate boundaries of regions harboring significant epigenetic modifications. Our algorithm takes the spatial distribution of CpGs into account for the enrichment assay, allowing for optimization of the definition of empirical regions for differential methylation. Combined with the dependent adjustment for regional p-value combination and DMR annotation, we provide a method that may be applied to a variety of datasets for rapid DMR analysis. Our method classifies both the directionality of DMRs and their genome-wide distribution, and we have observed that shows clinical relevance through correct stratification of two Acute Myeloid Leukemia (AML) tumor sub-types. Our weighted optimization algorithm eDMR for calling DMRs extends an established DMR R pipeline (methylKit) and provides a needed resource in epigenomics. Our method enables an accurate and scalable way of finding DMRs in high-throughput methylation sequencing experiments. eDMR is available for download at /edmr/ .
Publisher: Wiley
Date: 03-06-2020
DOI: 10.1111/BJH.16819
Publisher: Informa UK Limited
Date: 24-10-2019
Publisher: Wiley
Date: 28-11-2012
DOI: 10.1111/BJH.12131
Publisher: Elsevier BV
Date: 2011
Publisher: Springer Science and Business Media LLC
Date: 17-02-2020
DOI: 10.1186/S12881-020-0971-Z
Abstract: We report a large family with four successive generations, presenting with a complex phenotype of severe congenital neutropenia (SCN), partially penetrant monocytosis, and hearing loss of varying severity. We performed whole exome sequencing to identify the causative variants. Sanger sequencing was used to perform segregation analyses on remaining family members. We identified and classified a pathogenic GFI1 variant and a likely pathogenic variant in MYO6 which together explain the complex phenotypes seen in this family. We present a case illustrating the benefits of a broad screening approach that allows identification of oligogenic determinants of complex human phenotypes which may have been missed if the screening was limited to a targeted gene panel with the assumption of a syndromic disorder. This is important for correct genetic diagnosis of families and disentangling the range and severity of phenotypes associated with high impact variants.
Publisher: Springer Science and Business Media LLC
Date: 25-05-2017
DOI: 10.1007/S12185-017-2260-Y
Abstract: Recently, DDX41 mutations have been identified both as germline and acquired somatic mutations in families with multiple cases of late-onset myelodysplastic syndrome (MDS) and/or acute myeloid leukemia. The majority of germline mutations are frameshift mutations suggesting loss of function with DDX41 acting as a tumor suppressor, and there is a common somatic missense mutation found in a majority of germline mutated tumors. Clinically, DDX41 mutations lead to development of high-risk MDS at an age similar to that observed in sporadic cohorts, presenting a unique challenge to hematologists in recognizing the familial context. Functionally, DDX41 has been shown to contribute to multiple pathways and processes including mRNA splicing, innate immunity and rRNA processing. Mutations in DDX41 result in aberrations to each of these in ways that could potentially impact on tumorigenesis-initiation, maintenance or progression. This review discusses the various molecular, clinical and biological aspects of myeloid malignancy predisposition due to DDX41 mutation and highlights how each of these suggest potential therapeutic opportunities through the use of pathway-specific inhibitors.
Publisher: Hindawi Limited
Date: 12-10-2021
DOI: 10.1002/HUMU.24288
Publisher: American Society of Hematology
Date: 02-03-2022
Publisher: American Society of Hematology
Date: 22-04-2010
DOI: 10.1182/BLOOD-2009-08-235846
Abstract: Granulocyte/macrophage colony-stimulating factor promotes growth, survival, differentiation, and activation of normal myeloid cells and plays an important role in myeloid leukemias. The GM-CSF receptor (GMR) shares a signaling subunit, βc, with interleukin-3 and interleukin-5 receptors and has recently been shown to induce activation of Janus kinase 2 (JAK2) and downstream signaling via formation of a unique dodecameric receptor complex. In this study we use 2 activated βc mutants that display distinct signaling capacity and have differential requirements for the GMR α-subunit (GMR-α) to dissect the signaling pathways associated with the GM-CSF response. The V449E transmembrane mutant selectively activates JAK2/signal transducer and activator of transcription 5 and extracellular signal-regulated kinase (ERK) pathways, resulting in a high level of sensitivity to JAK and ERK inhibitors, whereas the extracellular mutant (FIΔ) selectively activates the phosphoinositide 3-kinase/Akt and IκKβ/nuclear factorκB pathways. We also demonstrate a novel and direct interaction between the SH3 domains of Lyn and Src with a conserved proline-rich motif in GMR-α and show a selective requirement for Src family kinases by the FIΔ mutant. We relate the nonoverlapping nature of signaling by the activated mutants to the structure of the unique GMR complex and propose alternative modes of receptor activation acting synergistically in the mature liganded receptor complex.
Publisher: Oxford University Press (OUP)
Date: 12-06-2006
DOI: 10.1189/JLB.0206112
Abstract: Mechanisms controlling the balance between proliferation and self-renewal versus growth suppression and differentiation during normal and leukemic myelopoiesis are not understood. We have used the bi-potent FDB1 myeloid cell line model, which is responsive to myelopoietic cytokines and activated mutants of the granulocyte macrophage-colony stimulating factor (GM-CSF) receptor, having differential signaling and leukemogenic activity. This model is suited to large-scale gene-profiling, and we have used a factorial time-course design to generate a substantial and powerful data set. Linear modeling was used to identify gene-expression changes associated with continued proliferation, differentiation, or leukemic receptor signaling. We focused on the changing transcription factor profile, defined a set of novel genes with potential to regulate myeloid growth and differentiation, and demonstrated that the FDB1 cell line model is responsive to forced expression of oncogenes identified in this study. We also identified gene-expression changes associated specifically with the leukemic GM-CSF receptor mutant, V449E. Signaling from this receptor mutant down-regulates CCAAT/enhancer-binding protein α (C/EBPα) target genes and generates changes characteristic of a specific acute myeloid leukemia signature, defined previously by gene-expression profiling and associated with C/EBPα mutations.
Publisher: Springer Science and Business Media LLC
Date: 23-06-2018
DOI: 10.1038/LEU.2017.196
Publisher: American Society of Hematology
Date: 07-07-2016
DOI: 10.1182/BLOOD-2015-12-684514
Abstract: Klf5 functions in hematopoiesis to regulate HSC and progenitor proliferation and localization in the bone marrow. Klf5 is required in the granulocyte lineage and positively affects neutrophil output at the expense of eosinophil production.
Publisher: Springer Science and Business Media LLC
Date: 13-04-2021
DOI: 10.1038/S41375-021-01246-W
Abstract: The majority of studies assessing the contribution of pathogenic germline variants (PGVs) to cancer predisposition have focused on patients with single cancers. We analyzed 45 known cancer predisposition genes (CPGs) in germline s les of 202 patients with hematological malignancies (HMs) plus one or more other independent cancer managed at major tertiary medical centers on two different continents. This included 120 patients with therapy-related myeloid neoplasms (t-MNs), where the HM occurred after cytotoxic treatment for a first malignancy, and 82 patients with multiple cancers in which the HM was not preceded by cytotoxic therapy (MC-HM). Using American College of Medical Genetics/Association for Molecular Pathology variant classification guidelines, 13% of patients had PGVs, most frequently identified in CHEK2 (17% of PGVs), BRCA1 (13%), DDX41 (13%), and TP53 (7%). The frequency of PGVs in MC-HM was higher than in t-MN, although not statistically significant (18 vs. 9% p = 0.085). The frequency of PGVs in lymphoid and myeloid HM patients was similar (19 vs. 17.5% p > 0.9). Critically, patients with PGVs in BRCA1, BRCA2 or TP53 did not satisfy current clinical phenotypic criteria for germline testing. Our data suggest that a personal history of multiple cancers, one being a HM, should trigger screening for PGVs.
Publisher: American Society of Hematology
Date: 24-03-2020
DOI: 10.1182/BLOODADVANCES.2019000901
Abstract: First reported in 1999, germline runt-related transcription factor 1 (RUNX1) mutations are a well-established cause of familial platelet disorder with predisposition to myeloid malignancy (FPD-MM). We present the clinical phenotypes and genetic mutations detected in 10 novel RUNX1-mutated FPD-MM families. Genomic analyses on these families detected 2 partial gene deletions, 3 novel mutations, and 5 recurrent mutations as the germline RUNX1 alterations leading to FPD-MM. Combining genomic data from the families reported herein with aggregated published data sets resulted in 130 germline RUNX1 families, which allowed us to investigate whether specific germline mutation characteristics (type, location) could explain the large phenotypic heterogeneity between patients with familial platelet disorder and different HMs. Comparing the somatic mutational signatures between the available familial (n = 35) and published sporadic (n = 137) RUNX1-mutated AML patients showed enrichment for somatic mutations affecting the second RUNX1 allele and GATA2. Conversely, we observed a decreased number of somatic mutations affecting NRAS, SRSF2, and DNMT3A and the collective genes associated with CHIP and epigenetic regulation. This is the largest aggregation and analysis of germline RUNX1 mutations performed to date, providing a unique opportunity to examine the factors underlying phenotypic differences and disease progression from FPD to MM.
Publisher: Springer Science and Business Media LLC
Date: 14-05-2019
DOI: 10.1038/S41375-019-0479-8
Abstract: Therapy-related myeloid neoplasms (T-MN) are poorly characterized secondary hematological malignancies following chemotherapy/radiotherapy exposure. We compared the clinical and mutational characteristics of T-MN (n = 129) and primary myelodysplastic syndrome (P-MDS, n = 108) patients. Although the somatic mutation frequency was similar between T-MN and P-MDS patients (93% in both groups), the pattern was distinct. TP53 mutations were more frequent in T-MN (29.5 vs. 7%), while spliceosomal complex mutations were more common in P-MDS (56.5 vs. 25.6%). In contrast to P-MDS, the ring sideroblasts (RS) phenotype was not associated with better survival in T-MN, most probably due to genetic association with TP53 mutations. SF3B1 was mutated in 96% of P-MDS with ≥15% RS, but in only 32% T-MN. TP53 mutations were detected in 92% T-MN with ≥15% RS and SF3B1 wild-type cases. Interestingly, T-MN and P-MDS patients with "Very low" or "Low" Revised International Prognostic Scoring System (IPSS-R) showed similar biological and clinical characteristics. In a Cox regression analysis, TP53 mutation was a poor prognostic factor in T-MN, independent of IPSS-R cytogenetics, disease-modifying therapy, and NRAS mutation. Our data have direct implications for T-MN management and provide evidence that, in addition to conventional disease parameters, mutational analysis should be incorporated in T-MN risk stratification.
Publisher: American Society of Hematology
Date: 17-02-2023
DOI: 10.1182/BLOODADVANCES.2022008172
Abstract: There is increasing recognition that pathogenic germ line variants drive the development of hematopoietic cancers in many in iduals. Currently, patients with hereditary hematologic malignancies (HHMs) receive similar standard therapies and hematopoietic stem cell transplant (HSCT) approaches as those with sporadic disease. We hypothesize that patients with myeloid malignancies and deleterious germ line predisposition variants have different posttransplant outcomes than those without such alleles. We studied 472 patients with myeloid neoplasms, of whom 26% had deleterious germ line variants and 34% underwent HSCT. Deleterious germ line variants in CHEK2 and DDX41 were most commonly seen in American and Australian cohorts, respectively. Patients with deleterious germ line DDX41 variants had a higher incidence of severe (stage 3-4) acute graft-versus-host disease (GVHD) (38%) than recipients with deleterious CHEK2 variants (0%), other HHM variants (12%), or patients without such germ line variants (9%) (P = .002). Importantly, the use of posttransplant cyclophosphamide reduced the risk of severe acute GVHD in patients receiving HSCT for deleterious germ line DDX41-associated myeloid neoplasms (0% vs 53%, P = .03). Based on these results, we advocate the use of posttransplant cyclophosphamide when in iduals with deleterious germ line DDX41 variants undergo allogeneic HSCT for myeloid malignancies, even when transplantation has been performed using wild-type donors.
Publisher: Springer Science and Business Media LLC
Date: 06-1201
Publisher: American Society of Hematology
Date: 02-12-2021
Publisher: Oxford University Press (OUP)
Date: 04-1999
DOI: 10.1093/HMG/8.4.611
Abstract: Parthenogenetic and normal blastocysts were compared using differential display analysis as a means to identify new imprinted genes. A single gene was identified with increased expression in parthenogenetic blastocysts, suggesting it might be an imprinted gene expressed from the maternally inherited allele. The gene, named Bex1 (brainexpressedX-linked gene), maps near Plp on the mouse X chromosome and to Xq22 in humans. Database homology searches revealed two additional uncharacterized cDNAs similar to Bex1 that were named Bex2 and Bex3. Allele-specific expression analysis of Bex1 using F1 blastocysts indicated an excess of transcript expressed from the maternally inherited allele compared with the paternally inherited allele. This excess level of transcript derived from the maternally inherited allele may be due to imprinted X inactivation of the paternally inherited allele in the extraembryonic lineages of female embryos rather than a result of genomic imprinting.
Publisher: Informa UK Limited
Date: 07-2003
Publisher: Ferrata Storti Foundation (Haematologica)
Date: 28-03-2019
Publisher: American Society of Hematology
Date: 30-06-2022
Abstract: Inducing cell death by the sphingolipid ceramide is a potential anticancer strategy, but the underlying mechanisms remain poorly defined. In this study, triggering an accumulation of ceramide in acute myeloid leukemia (AML) cells by inhibition of sphingosine kinase induced an apoptotic integrated stress response (ISR) through protein kinase R–mediated activation of the master transcription factor ATF4. This effect led to transcription of the BH3-only protein Noxa and degradation of the prosurvival Mcl-1 protein on which AML cells are highly dependent for survival. Targeting this novel ISR pathway, in combination with the Bcl-2 inhibitor venetoclax, synergistically killed primary AML blasts, including those with venetoclax-resistant mutations, as well as immunophenotypic leukemic stem cells, and reduced leukemic engraftment in patient-derived AML xenografts. Collectively, these findings provide mechanistic insight into the anticancer effects of ceramide and preclinical evidence for new approaches to augment Bcl-2 inhibition in the therapy of AML and other cancers with high Mcl-1 dependency.
Publisher: Springer Science and Business Media LLC
Date: 15-07-2022
Publisher: Hindawi Limited
Date: 31-08-2021
DOI: 10.1002/HUMU.24271
Publisher: American Society for Clinical Investigation
Date: 09-2021
DOI: 10.1172/JCI152464
Publisher: Springer Science and Business Media LLC
Date: 08-01-2009
DOI: 10.1038/LEU.2008.349
Abstract: The tumor suppressor Gadd45alpha was earlier shown to be a repressed target of sustained receptor-mediated ERK1/2 signaling. We have identified Gadd45alpha as a downregulated gene in response to constitutive signaling from two FLT3 mutants (FLT3-ITD and FLT3-TKD) commonly found in AML, and a leukemogenic GM-CSF receptor trans-membrane mutant (GMR-V449E). GADD45A mRNA downregulation is also associated with FLT3-ITD(+) AML. Sustained ERK1/2 signaling contributes significantly to receptor-mediated downregulation of Gadd45alpha mRNA in FDB1 cells expressing activated receptor mutants, and in the FLT3-ITD(+) cell line MV4 . Knockdown of Gadd45alpha with shRNA led to increased growth and survival of FDB1 cells and enforced expression of Gadd45alpha in FDB1 cells expressing FLT3-ITD or GMR-V449E resulted in reduced growth and viability. Gadd45alpha overexpression in FLT3-ITD(+) AML cell lines also resulted in reduced growth associated with increased apoptosis and G(1)/S cell cycle arrest. Overexpression of Gadd45alpha in FDB1 cells expressing GMR-V449E was sufficient to induce changes associated with myeloid differentiation suggesting Gadd45alpha downregulation contributes to the maintenance of receptor-induced myeloid differentiation block. Thus, we show that ERK1/2-mediated downregulation of Gadd45alpha by sustained receptor signaling contributes to growth, survival and arrested differentiation in AML.
Publisher: American Society of Hematology
Date: 30-08-2018
DOI: 10.1182/BLOOD-2018-02-832253
Abstract: Next-generation sequencing revealed variants in cancer-associated genes at diagnosis of CML more frequently in patients with poor outcomes. All patients at BC had mutated cancer genes, including fusions, that predated BCR-ABL1 kinase domain mutations in a majority.
Publisher: Elsevier BV
Date: 2012
DOI: 10.1016/J.LEUKRES.2011.09.013
Abstract: Krüppel-like factor 5 (KLF5) has been implicated as a tumor suppressor in various solid tumors such as breast and prostate, and recent studies have demonstrated a role for this protein in neutrophil differentiation of acute promyelocytic leukemia cells in response to ATRA. Here, we show that KLF5 expression increases during primary granulocyte differentiation and that expression of KLF5 is a requirement for granulocyte differentiation of 32D cells. In AML, we show that KLF5 mRNA expression levels are reduced in multiple French-American-British subtypes compared to normal controls, and also in leukemic stem cells relative to normal hematopoietic stem cells. We demonstrate that in selected AML cases, reduced expression is associated with hypermethylation of the KLF5 locus in the proximal promoter and/or intron 1, suggesting that this may represent a Class II genetic lesion in the development of AML.
Publisher: Springer Science and Business Media LLC
Date: 09-02-2016
DOI: 10.1038/LEU.2016.24
Publisher: American Society of Hematology
Date: 24-11-2022
Abstract: Myeloid neoplasms and acute leukemias derive from the clonal expansion of hematopoietic cells driven by somatic gene mutations. Although assessment of morphology plays a crucial role in the diagnostic evaluation of patients with these malignancies, genomic characterization has become increasingly important for accurate diagnosis, risk assessment, and therapeutic decision making. Conventional cytogenetics, a comprehensive and unbiased method for assessing chromosomal abnormalities, has been the mainstay of genomic testing over the past several decades and remains relevant today. However, more recent advances in sequencing technology have increased our ability to detect somatic mutations through the use of targeted gene panels, whole-exome sequencing, whole-genome sequencing, and whole-transcriptome sequencing or RNA sequencing. In patients with myeloid neoplasms, whole-genome sequencing represents a potential replacement for both conventional cytogenetic and sequencing approaches, providing rapid and accurate comprehensive genomic profiling. DNA sequencing methods are used not only for detecting somatically acquired gene mutations but also for identifying germline gene mutations associated with inherited predisposition to hematologic neoplasms. The 2022 International Consensus Classification of myeloid neoplasms and acute leukemias makes extensive use of genomic data. The aim of this report is to help physicians and laboratorians implement genomic testing for diagnosis, risk stratification, and clinical decision making and illustrates the potential of genomic profiling for enabling personalized medicine in patients with hematologic neoplasms.
Publisher: American Society of Hematology
Date: 12-10-2023
DOI: 10.1182/BLOODADVANCES.2023010045
Abstract: In iduals with germline variants associated with hereditary hematopoietic malignancies (HHMs) have a highly variable risk for leukemogenesis. Gaps in our understanding of pre-malignant states in HHMs have h ered efforts to design effective clinical surveillance programs, provide personalized pre-emptive treatments and inform appropriate counselling for patients. We used the largest known comparative international cohort of germline RUNX1, GATA2, or DDX41 variant carriers without and with hematopoietic malignancies (HMs) to identify patterns of genetic drivers that are unique to each HHM syndrome before and after leukemogenesis. These patterns included striking heterogeneity in rates of early-onset clonal hematopoiesis (CH), with a high prevalence of CH in RUNX1 and GATA2 variant carriers who did not have malignancies ("carriers-without HM"). We observed a paucity of CH in DDX41 carriers-without HM. In RUNX1 carriers-without HM with CH, we detected variants in TET2, PHF6, and, most frequently, BCOR. These genes were recurrently mutated in RUNX1-driven malignancies, suggesting CH is a direct precursor to malignancy in RUNX1-driven HHMs. Leukemogenesis in RUNX1 and DDX41 carriers was often driven by second-hits in RUNX1 and DDX41, respectively. This study may inform the development of HHM-specific clinical trials and gene-specific approaches to clinical monitoring. For ex le, trials investigating the potential benefits of monitoring DDX41 carriers-without HM for low-frequency second hits in DDX41 may now be beneficial. Similarly, trials monitoring carriers-without HM with RUNX1 germline variants for the acquisition of somatic variants in BCOR, PHF6, TET2, and second hits in RUNX1 are warranted.
Publisher: American Society of Hematology
Date: 23-08-2021
DOI: 10.1182/BLOODADVANCES.2021004653
Abstract: Germline RUNX1 mutations underlie a syndrome, RUNX1-familial platelet disorder (RUNX1-FPD), characterized by bleeding symptoms that result from quantitative and/or qualitative defect in platelets and a significantly increased risk for developing hematologic malignancies. Myeloid neoplasms are the most commonly diagnosed hematologic malignancies, followed by lymphoid malignancies of T-cell origin. Here, we describe the first 2 cases of B-cell acute lymphoblastic leukemia (B-ALL) in patients with confirmed germline RUNX1 mutations. While 1 of the patients had a known diagnosis of RUNX1-FPD with a RUNX1 p.P240Hfs mutation, the other was the index patient of a kindred with a novel RUNX1 variant, RUNX1 c.587C& T (p.T196I), noted on a targeted genetic testing of the B-ALL diagnostic s le. We discuss the clinical course, treatment approaches, and the outcome for the 2 patients. Additionally, we describe transient resolution of the mild thrombocytopenia and bleeding symptoms during therapy, as well as the finding of clonal hematopoiesis with a TET2 mutant clone in 1 of the patients. It is critical to consider testing for germline RUNX1 mutations in patients presenting with B-ALL who have a personal or family history of thrombocytopenia, bleeding symptoms, or RUNX1 variants identified on genetic testing at diagnosis.
Publisher: Springer Science and Business Media LLC
Date: 12-05-2022
DOI: 10.1038/S41467-022-30223-9
Abstract: The interaction of germline variation and somatic cancer driver mutations is under-investigated. Here we describe the genomic mitochondrial landscape in adult acute myeloid leukaemia (AML) and show that rare variants affecting the nuclear- and mitochondrially-encoded complex I genes show near-mutual exclusivity with somatic driver mutations affecting isocitrate dehydrogenase 1 ( IDH1 ), but not IDH2 suggesting a unique epistatic relationship. Whereas AML cells with rare complex I variants or mutations in IDH1 or IDH2 all display attenuated mitochondrial respiration, heightened sensitivity to complex I inhibitors including the clinical-grade inhibitor, IACS-010759, is observed only for IDH1 -mutant AML. Furthermore, IDH1 mutant blasts that are resistant to the IDH1-mutant inhibitor, ivosidenib, retain sensitivity to complex I inhibition. We propose that the IDH1 mutation limits the flexibility for citrate utilization in the presence of impaired complex I activity to a degree that is not apparent in IDH2 mutant cells, exposing a mutation-specific metabolic vulnerability. This reduced metabolic plasticity explains the epistatic relationship between the germline complex I variants and oncogenic IDH1 mutation underscoring the utility of genomic data in revealing metabolic vulnerabilities with implications for therapy.
Publisher: American Society of Hematology
Date: 26-11-2009
DOI: 10.1182/BLOOD-2009-02-204818
Abstract: Deregulated cell survival programs are a classic hallmark of cancer. We have previously identified a serine residue (Ser585) in the βc subunit of the granulocyte-macrophage colony-stimulating factor receptor that selectively and independently promotes cell survival. We now show that Ser585 phosphorylation is constitutive in 20 (87%) of 23 acute myeloid leukemia (AML) patient s les, indicating that this survival-only pathway is frequently deregulated in leukemia. We performed a global expression screen to identify gene targets of this survival pathway and report a 138-gene βc Ser585-regulated transcriptome. Pathway analysis defines a gene network enriched for PI3-kinase target genes and a cluster of genes involved in cancer and cell survival. We show that one such gene, osteopontin (OPN), is a functionally relevant target of the Ser585-survival pathway as shown by siRNA-mediated knockdown of OPN expression that induces cell death in both AML blasts and CD34+CD38−CD123+ leukemic progenitors. Increased expression of OPN at diagnosis is associated with poor prognosis with multivariate analysis indicating that it is an independent predictor of overall patient survival in normal karyotype AML (n = 60 HR = 2.2 P = .01). These results delineate a novel cytokine-regulated Ser585/PI3-kinase signaling network that is deregulated in AML and identify OPN as a potential prognostic and therapeutic target.
Publisher: American Society of Hematology
Date: 29-07-2022
Publisher: Wiley
Date: 25-03-2013
DOI: 10.1111/BJH.12295
Publisher: American Society of Hematology
Date: 25-02-2016
DOI: 10.1182/BLOOD-2015-10-676098
Abstract: Novel missense germ line DDX41 mutations define an earlier age of onset of hematologic malignancies than loss-of-function alleles. Carriers of DDX41 germ line mutations usually have normal blood counts until a myeloid or lymphoid malignancy develops.
Publisher: Springer Science and Business Media LLC
Date: 29-04-2010
DOI: 10.1038/LEU.2010.85
Publisher: Springer Science and Business Media LLC
Date: 20-06-2016
DOI: 10.1038/NM.4125
Publisher: Springer Science and Business Media LLC
Date: 04-07-2018
DOI: 10.1038/LEU.2017.210
Abstract: Prognostic gene expression signatures have been proposed as clinical tools to clarify therapeutic options in acute myeloid leukemia (AML). However, these signatures rely on measuring large numbers of genes and often perform poorly when applied to independent cohorts or those with older patients. Long intergenic non-coding RNAs (lincRNAs) are emerging as important regulators of cell identity and oncogenesis, but knowledge of their utility as prognostic markers in AML is limited. Here we analyze transcriptomic data from multiple cohorts of clinically annotated AML patients and report that (i) microarrays designed for coding gene expression can be repurposed to yield robust lincRNA expression data, (ii) some lincRNA genes are located in close proximity to hematopoietic coding genes and show strong expression correlations in AML, (iii) lincRNA gene expression patterns distinguish cytogenetic and molecular subtypes of AML, (iv) lincRNA signatures composed of three or four genes are independent predictors of clinical outcome and further dichotomize survival in European Leukemia Net (ELN) risk groups and (v) an analytical tool based on logistic regression analysis of quantitative PCR measurement of four lincRNA genes (LINC4) can be used to determine risk in AML.
Publisher: Springer Science and Business Media LLC
Date: 09-03-2015
DOI: 10.1038/LEU.2015.67
Publisher: Elsevier BV
Date: 02-2023
DOI: 10.1016/J.PATHOL.2022.05.015
Abstract: The identification of a somatic mutation associated with myeloid malignancy is of diagnostic importance in myeloproliferative neoplasms (MPNs). In iduals with no mutation detected in common screening tests for variants in JAK2, CALR, and MPL are described as 'triple-negative' and pose a diagnostic challenge if there is no other evidence of a clonal disorder. To identify potential drivers that might explain the clinical phenotype, we used an extended sequencing panel to characterise a cohort of 44 previously diagnosed triple-negative MPN patients for canonical mutations in JAK2, MPL and CALR at low variant allele frequency (found in 4/44 patients), less common variants in the JAK-STAT signalling pathway (12 patients), or other variants in recurrently mutated genes from myeloid malignancies (18 patients), including hotspot variants of potential clinical relevance in eight patients. In one patient with thrombocytosis we identified biallelic germline MPL variants. Neither MPL variant was activating in cell proliferation assays, and one of the variants was not expressed on the cell surface, yet co-expression of both variants led to thrombopoietin hypersensitivity. Our results highlight the clinical value of extended sequencing including germline variant analysis and illustrate the need for detailed functional assays to determine whether rare variants in JAK2 or MPL are pathogenic.
Publisher: Wiley
Date: 18-10-2022
DOI: 10.1111/BJH.17855
Abstract: Over the last decade, the field of hereditary haematological malignancy syndromes (HHMSs) has gained increasing recognition among clinicians and scientists worldwide. Germline mutations now account for almost 10% of adult and paediatric myelodysplasia/acute myeloid leukaemia (MDS/AML). As our ability to diagnose HHMSs has improved, we are now faced with the challenges of integrating these advances into routine clinical practice for patients with MDS/AML and how to optimise management and surveillance of patients and asymptomatic carriers. Discoveries of novel syndromes combined with clinical, genetic and epigenetic profiling of tumour s les, have highlighted unique patterns of disease evolution across HHMSs. Despite these advances, causative lesions are detected in less than half of familial cases and evidence-based guidelines are often lacking, suggesting there is much still to learn. Future research efforts are needed to sustain current momentum within the field, led not only by advancing genetic technology but essential collaboration between clinical and academic communities.
Publisher: American Society of Hematology
Date: 16-10-2019
DOI: 10.1182/BLOODADVANCES.2019000644
Abstract: The ClinGen MM-VCEP has specified RUNX1-specific curation rules to address gene function, gene-specific domains, and phenotypic criteria. RUNX1-specific criteria resulted in a reduction in CONF and VUS variants by 33%, emphasizing the need for expert variant curation.
Publisher: Springer Science and Business Media LLC
Date: 11-04-2023
DOI: 10.1038/S41408-023-00821-X
Abstract: Revised diagnostic criteria for myeloid neoplasms (MN) issued by the International Consensus Classification (ICC) and the World Health Organization (WHO) recommended major change pertaining to TP53 -mutated ( TP53 mut ) MN. However, these assertions have not been specifically examined in therapy-related myeloid neoplasm (t-MN), a subset enriched with TP53 mut . We analyzed 488 t-MN patients for TP53 mut . At least one TP53 mut with variant allele frequency (VAF) ≥ 2% with or without loss of TP53 locus was noted in 182 (37.3%) patients and 88.2% of TP53 mut t-MN had a VAF ≥10%. TP53 mut t-MN with VAF ≥ 10% had a distinct clinical and biological profile compared to both TP53 mut VAF 10% and wild-type TP53 ( TP53 wt ) cases. Notably, TP53 mut VAF ≥ 10% had a significantly shorter survival compared to TP53 wt (8.3 vs. 21.6 months P 0.001), while the survival of TP53 mut VAF 10% was comparable to TP53 wt . Within TP53 mut VAF ≥ 10% cohort, the inferior outcomes persisted irrespective of the single- or multi-hit status, co-mutation pattern, or treatments received. Finally, survival of TP53 mut patients was poor across all the blast categories and MDS patients with % blasts had inferior survival compared to %. In summary, TP53 mut VAF ≥10% signified a clinically and molecularly homogenous cohort regardless of the allelic status.
Publisher: American Society of Hematology
Date: 24-02-2022
Publisher: Springer Science and Business Media LLC
Date: 04-09-2011
DOI: 10.1038/NG.913
No related grants have been discovered for Anna Brown.