Deletion of SPRY4 is a frequent event in secondary acute myeloid leukemia.
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ABSTRACT:
SUBMITTER: Geiger O
PROVIDER: S-EPMC5024751 | biostudies-literature | 2015 Nov
REPOSITORIES: biostudies-literature
Publications
Deletion of SPRY4 is a frequent event in secondary acute myeloid leukemia.
Geiger Olivia O Hatzl Stefan S Kashofer Karl K Hoefler Gerald G Wölfler Albert A Sill Heinz H Zebisch Armin A
Annals of hematology 20150725 11
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Project description:BackgroundThe myelodysplastic syndromes are a group of hematologic disorders that often evolve into secondary acute myeloid leukemia (AML). The genetic changes that underlie progression from the myelodysplastic syndromes to secondary AML are not well understood.MethodsWe performed whole-genome sequencing of seven paired samples of skin and bone marrow in seven subjects with secondary AML to identify somatic mutations specific to secondary AML. We then genotyped a bone marrow sample obtained during the antecedent myelodysplastic-syndrome stage from each subject to determine the presence or absence of the specific somatic mutations. We identified recurrent mutations in coding genes and defined the clonal architecture of each pair of samples from the myelodysplastic-syndrome stage and the secondary-AML stage, using the allele burden of hundreds of mutations.ResultsApproximately 85% of bone marrow cells were clonal in the myelodysplastic-syndrome and secondary-AML samples, regardless of the myeloblast count. The secondary-AML samples contained mutations in 11 recurrently mutated genes, including 4 genes that have not been previously implicated in the myelodysplastic syndromes or AML. In every case, progression to acute leukemia was defined by the persistence of an antecedent founding clone containing 182 to 660 somatic mutations and the outgrowth or emergence of at least one subclone, harboring dozens to hundreds of new mutations. All founding clones and subclones contained at least one mutation in a coding gene.ConclusionsNearly all the bone marrow cells in patients with myelodysplastic syndromes and secondary AML are clonally derived. Genetic evolution of secondary AML is a dynamic process shaped by multiple cycles of mutation acquisition and clonal selection. Recurrent gene mutations are found in both founding clones and daughter subclones. (Funded by the National Institutes of Health and others.).
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Project description:The value of event-free survival (EFS) as an end point in acute myeloid leukemia (AML) trials has been questioned. We hypothesized that rather than a surrogate for overall survival (OS), improvement in EFS may decrease the use of health care. In this retrospective study, we identified 400 patients with AML who were treated on first-line therapy trials and had OS between 2 and 36 months. We captured health care use from diagnosis until death or until the patient was censored at stem cell transplantation (SCT). We used correlation and regression analysis to determine the relation between health care use and EFS. Among patients with newly diagnosed AML, 35% had adverse-risk AML, 48% received intensive chemotherapy, and 28% received hypomethylating agents. The median EFS censored at SCT was 9.7 months. Longer EFS led to a significant decline in health care use regardless of OS. This held true for all observations, including overall health care use (r = -0.45), sum of clinic visits, emergency room visits, hospitalizations, consultations (r = -0.44), sum of invasive procedures, laboratory and imaging studies (r = -0.51), and blood product transfusions (r = -0.19). These correlations were stronger for patients who achieved a complete remission and held true across age, treatment, and disease risk subgroups. In patients with newly diagnosed AML, improvement in EFS correlates with a decrease in all health care use irrespective of OS duration.
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Project description:Kinases such as MEK are attractive targets for novel therapy in cancer, including acute myeloid leukaemia (AML). Acquired and inherent resistance to kinase inhibitors, however, is becoming an increasingly important challenge for the clinical success of such therapeutics, and often arises from mutations in the drug-binding domain of the target kinase. To identify possible causes of resistance to MEK inhibition, we generated a model of resistance by long-term treatment of AML cells with AZD6244 (selumetinib). Remarkably, resistance to MEK inhibition was due to acquired PTEN haploinsufficiency, rather than mutation of MEK. Resistance via this mechanism was confirmed using CRISPR/Cas9 technology targeting exon 5 of PTEN. While PTEN loss has been previously implicated in resistance to a number of other therapeutic agents, this is the first time that it has been shown directly and in AML.
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Project description:The characterization of the molecular landscape and the advent of targeted therapies have defined a new era in the prognostication and treatment of acute myeloid leukemia. Recent revisions in the European LeukemiaNet 2022 guidelines have refined the molecular, cytogenetic, and treatment-related boundaries between myelodysplastic neoplasms (MDS) and AML. This review details the molecular mechanisms and cellular pathways of myeloid maturation aberrancies contributing to dysplasia and leukemogenesis, focusing on recent molecular categories introduced in ELN 2022. We provide insights into novel and rational therapeutic combination strategies that exploit mechanisms of leukemogenesis, highlighting the underpinnings of splicing factors, the cohesin complex, and chromatin remodeling. Areas of interest for future research are summarized, and we emphasize approaches designed to advance existing treatment strategies.
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