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The clinical and prognostic relevance of driver mutations in 203 Taiwanese patients with primary myelofibrosis


Aims We investigated the clinical and prognostic relevance of the mutational status of driver genes with allele burden and endogenous erythroid colony (EEC) growth in 203 Taiwanese patients with primary myelofibrosis (PMF).

Methods Pyrosequencing was used to detect JAK2V617F mutational status and measure allele burden, while MPL (exon 10) mutations were analysed by PCR assay and then by direct sequencing. CALR exon 9 mutations were first screened for length changes by GeneScan followed by sequencing. The allele burden of the mutated CALR gene was measured by pyrosequencing. The EEC assay was conducted using a serum-free culture system.

Results The frequencies of the three driver mutations and triple-negative status were similarly distributed between pre-PMF and overt PMF patients, except that pre-PMF patients had a higher incidence of CALR type 2/type-2 like mutations and a lower JAK2V617F allele burden. EEC growth and CALR mutations conferred favourable overall survival (OS). A lower JAK2V617F allele burden and grade 3 bone marrow fibrosis were associated with shorter OS and decreased leukaemia-free survival (LFS). Type 2/type 2-like CAL mutations were associated with better LFS compared with type1/type 1-like mutations. Patients with triple-negative mutation status had significantly worse OS and LFS. The allele burden of CALR mutations remained unchanged, while some JAK2V617F mutations showed clonal expansion in patients during secondary acute myeloid leukaemia transformation.

Conclusions Our study showed that EEC growth, a higher JAK2V617F allele burden and CALR mutations, especially type 2, were independent predictors for better outcomes in PMF. The allele burden of CALR mutations remained stable, but the allele burden of JAK2V617Fmutations was variable during leukaemia transformation.

  • molecular genetics
  • leukaemia
  • myelofibrosis

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  • Handling editor Mary Frances McMullin.

  • Contributors L-YS: designed the study, collected patient samples and clinical data, performed the biomarker analyses, analysed the results and wrote the paper; M-CK: collected patient samples and clinical data, performed the literature review and wrote the paper; C-FS: reviewed the bone marrow biopsies; Y-JH: performed biomarker analyses; T-YH: compiled molecular genetic data, pathological findings and clinical data; T-LL, J-HW, P-NW and HC: provided patient clinical data; T-HL: performed statistical analyses.

  • Funding This study was supported in part by grants from Chang Gung Memorial Hospital, Taiwan (CMRPG3D1533) and the Ministry of Health and Welfare, Taiwan (DOH102-TD-C-111-006 and MOHW105-TDU-B-212-134005).

  • Competing interests None declared.

  • Ethics approval The study was approved by the Institutional Review Board of Chang Gung Memorial Hospital.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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