Single cell RNA sequencing of chronic myelomonocytic leukemia stem cell

ABSTRACT: Chronic myelomonocyticleukemia (CMML) is a clinically heterogeneous stem cell malignancy with overlapping features of myelodysplasiaand myeloproliferation. CMML is further subclassified according to percentage of leukemic blasts present in blood or bone marrow, reflecting its intrinsic tendency to progression towards acute myeloid leukemia. Over 90% of CMML patients carry founding mutations in epigenetic and/or splicing genes, which typically involve the primitive stem cell compartment. Thus, transcriptional dysregulation at the stem cell level is likely fundamental to disease onset and progression. However, the critical early hematopoietic stem and progenitor cell (HSPC) subpopulation has not been studied in CMML. We performed single cell RNA sequencing on>6,800 Lin-CD34+CD38-primitive HSPCs from seven CMML patients and three healthy controls. We found substantial inter-and intra-patient heterogeneity, with CMML stem cells displaying distinct transcriptional programs, differentiation potential and cellular signaling pathway priming. Pseudotime analyses revealed that CMML-1/CMML-2 HSPCs have distinct cellular trajectories, indicating that transformation events initiate early within the hematopoietic hierarchy and suggesting against a simple linear clonal evolution dynamic in acute leukemic transformation. We further identified several transcription factors uniquely active in distinct sample subsets. Together our findings provide novel insights into the CMML stem cell compartment, revealing an unexpected degree of transcriptional and subclonal heterogeneity and highlighting early mediators of disease initiation and transformation, of potential translational importance

INSTRUMENT(S): NextSeq 500

ORGANISM(S): Homo sapiens

SUBMITTER: Kiran Batta 

PROVIDER: E-MTAB-8884 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress