Abstract Number: LPB0029
Meeting: ISTH 2021 Congress
Background: Single-cell sequencing of hematopoietic stem cells (HSCs) provides an unprecedented opportunity to directly reveal origins of driver mutations in essential thrombocythemia (ET)–a unique model for dissecting clonal architecture of tumors.
Aims: The study aimed at revealing the clonal mutation patterns of ET with different driver mutations.
Methods: Whole-exome sequencing of bulk bone marrow cells from 33 ET patients were conducted, and targeted region sequencing of single HSCs from two representative patients was performed, one with JAK2 V617F and the other one with the CALR mutation.
Results: Seventeen patients (51.5%) had the JAK2 V617F mutation, four (10.8%) harbored the CALR mutations. More somatic non-silent mutations were observed in JAK2 V617F+ patients than in CALR-mutated patients (P=0.048). Mutations with known roles in myeloid neoplasms were more likely to co-occur with JAK2 V617F. Single-HSC sequencing revealed that not every possible key mutation identified in bulk cells was an ‘essential mutation’. In the JAK2 V617F+ patient, tumor cells were oligoclonal in origin. The JAK2 V617F mutation occurred after the LIN54, TET2, and DNMT3A mutations. These pre-JAK2 mutations randomly occurred and continually accumulated in almost all cells from the HSC pool. JAK2 V617F occurred in cells with at least one of the pre-JAK2 mutations. As a consequence, a cluster of cells with these four mutations in every cell were emerged and acquired a growth advantage. Unlike JAK2 V617F, the CALR mutation was an early event, and the clone containing a single CALR mutation acquire a survival advantage. JAK2 V617F+ cell amplification mainly occurred in the HSC compartment in ET30, but CALR-mutated cells were mainly amplified in HPCs in ET35. This observation helps explain why JAK2 V617F causes erythrocytosis, granulocytosis, and thrombocytosis, while the CALR mutations mainly cause thrombocytosis.
Conclusions: Single-HSC sequencing provides direct evidence for revealing subject-specific key mutations and clonal evolution patterns in patients with ET.
To cite this abstract in AMA style:Fu R, Liu D, Xiong H, Su H, Li H, Liu X, Xue F, Zhu S, Yang R, Cheng T, Zhang L. Distinct Clonal Mutation Patterns between JAK2 V617F Positive and CALR-mutated Essential Thrombocythemia [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/distinct-clonal-mutation-patterns-between-jak2-v617f-positive-and-calr-mutated-essential-thrombocythemia/. Accessed October 2, 2023.
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