Dataset Information

Stem cell mutations can be detected in myeloma patients years before onset of secondary leukemias.

ABSTRACT: Therapy-related acute myeloid leukemia and myelodysplastic syndromes (t-AML/t-MDS) are secondary hematologic malignancies associated with poor prognosis, warranting insights into their predisposing conditions and cells of origin. We identified patients with myeloma who developed t-AML/t-MDS and analyzed their stem and progenitor cells collected years before the onset of secondary disease. We demonstrate that aberrant stem cells with high CD123 expression can be detected long before the onset of overt leukemia. Rigorous sorting, followed by targeted sequencing, resulted in ultradeep functional depth of sequencing and revealed preexisting mutant hematopoietic stem cell (HSC) clones, mainly harboring TP53 mutations, that became the dominant population at the time of leukemic presentation. Taken together, these data show that HSCs can act as reservoirs for leukemia-initiating cells many years before the onset of myeloid leukemia.

SUBMITTER: Sridharan A

PROVIDER: S-EPMC6963234 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Stem cell mutations can be detected in myeloma patients years before onset of secondary leukemias.

Sridharan Ashwin A Schinke Carolina D CD Georgiev George G Da Silva Ferreira Mariana M Thiruthuvanathan Victor V MacArthur Ian I Bhagat Tushar D TD Choudhary Gaurav S GS Aluri Srinivas S Chen Jiahao J Pradhan Kith K Xia Yu Y Panjikaran Maya M Sims Gregory G Bhagat Chirag K CK Bender Ryan R Keeler Lauryn L Graber Armin A Heuck Christoph C Fletcher Frederick A FA Alapat Daisy D Weinhold Niels N Johnson Sarah K SK Wickrema Amittha A Barlogie Bart B Morgan Gareth J GJ Shastri Aditi A Steidl Ulrich U Will Britta B Verma Amit A

Blood advances 20191201 23

Therapy-related acute myeloid leukemia and myelodysplastic syndromes (t-AML/t-MDS) are secondary hematologic malignancies associated with poor prognosis, warranting insights into their predisposing conditions and cells of origin. We identified patients with myeloma who developed t-AML/t-MDS and analyzed their stem and progenitor cells collected years before the onset of secondary disease. We demonstrate that aberrant stem cells with high CD123 expression can be detected long before the onset of ...[more]

PMID: 31805192

Similar Datasets

Project description:BackgroundLeprosy, a chronic infectious disease caused by Mycobacterium leprae, is often late- or misdiagnosed leading to irreversible disabilities. Blood transcriptomic biomarkers that prospectively predict those who progress to leprosy (progressors) would allow early diagnosis, better treatment outcomes and facilitate interventions aimed at stopping bacterial transmission. To identify potential risk signatures of leprosy, we collected whole blood of household contacts (HC, n=5,352) of leprosy patients, including individuals who were diagnosed with leprosy 4-61 months after sample collection.MethodsWe investigated differential gene expression (DGE) by RNA-Seq between progressors before presence of symptoms (n=40) and HC (n=40), as well as longitudinal DGE within each progressor. A prospective leprosy signature was identified using a machine learning approach (Random Forest) and validated using reverse transcription quantitative PCR (RT-qPCR).FindingsAlthough no significant intra-individual longitudinal variation within leprosy progressors was identified, 1,613 genes were differentially expressed in progressors before diagnosis compared to HC. We identified a 13-gene prospective risk signature with an Area Under the Curve (AUC) of 95.2%. Validation of this RNA-Seq signature in an additional set of progressors (n=43) and HC (n=43) by RT-qPCR, resulted in a final 4-gene signature, designated RISK4LEP (MT-ND2, REX1BD, TPGS1, UBC) (AUC=86.4%).InterpretationThis study identifies for the first time a prospective transcriptional risk signature in blood predicting development of leprosy 4 to 61 months before clinical diagnosis. Assessment of this signature in contacts of leprosy patients can function as an adjunct diagnostic tool to target implementation of interventions to restrain leprosy development.FundingThis study was supported by R2STOP Research grant, the Order of Malta-Grants-for-Leprosy-Research, the Q.M. Gastmann-Wichers Foundation and the Leprosy Research Initiative (LRI) together with the Turing Foundation (ILEP# 702.02.73 and # 703.15.07).

Dataset Information

Stem cell mutations can be detected in myeloma patients years before onset of secondary leukemias.

Publications

Stem cell mutations can be detected in myeloma patients years before onset of secondary leukemias.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets