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Series GSE114115 Query DataSets for GSE114115
Status Public on Apr 14, 2020
Title Functional heterogeneity exceeds genetic heterogeneity in chronic myelomonocytic leukemia
Organism Homo sapiens
Experiment type Methylation profiling by high throughput sequencing
Summary The respective role of genetic and epigenetic heterogeneity in the functional diversity of cells that compose human malignancies remains poorly understood. This question is addressed in chronic myelomonocytic leukemia (CMML), a myeloid neoplasm in which clinical diversity contrasts with a limited genetic heterogeneity. By reprogramming CMML-patient and healthy donor CD34-positive cells, we generated induced pluripotent cell clones (iPSC). In one of the patients, we captured a part of the genetic heterogeneity of the leukemic clone and analyzed five iPSCs with two distinct genetic backgrounds, i.e. with and without KRASG12D mutation. Hematopoietic differentiation of these clones recapitulated the main features of the patient disease, including overproduction of granulomonocytes and dysmegakaryopoiesis. These analyses also disclosed significant discrepancies in the behavior as well as the DNA methylation pattern of hematopoietic cells derived from iPSCs with similar genetic background. Introduction of SRSF2P95H mutation in a KRAS-mutated iPSC partially suppressed the functional and epigenetic gap with the other KRAS-mutated clone. Despite the similar functional behavior of these two clones, only the SRSF2P95H clone responded to low doses of the hypomethylating agent decitabine by restoration of a more balanced production of hematopoietic cells. These analyses unravel additional levels of intraclonal heterogeneity beyond the coding mutations, which may also modulate individual cell response to treatment.
Overall design Twenty-five ng of high-molecular weight genomic DNA of CD34+ from control or patient A iPS clones were used to perform the ERRBS assay as described (Park et al. 2014) and sequenced on a HiSeq 3000 Illumina sequencer. 11 samples were analyzed, 6 iPS clones derived from a CMML patient and 5 derived from 2 different healthy control individuals.
Contributor(s) Beke A, Laplane L, Rivière J, Torres-Martin M, Rameau P, Saada V, Hurtado A, Oeuvray C, Lordier L, Leveque K, Vainchenker W, Figueroa ME, Droin N, Solary É
Citation(s) 31048357
Submission date May 07, 2018
Last update date Apr 14, 2020
Contact name Maria Eugenia Figueroa
Organization name University of Miiami
Department Human Genetics
Lab Maria Figueroa
Street address 1501 NW 10th Ave, BRB 709A, Locator code C227
City Miami
State/province FL
ZIP/Postal code 33136
Country USA
Platforms (1)
GPL21290 Illumina HiSeq 3000 (Homo sapiens)
Samples (10)
GSM3133008 A1
GSM3133009 A2
GSM3133010 A3
BioProject PRJNA464355
SRA SRP144749

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Supplementary file Size Download File type/resource
GSE114115_RAW.tar 261.5 Mb (http)(custom) TAR (of TXT)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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