Disease burden at the progenitor level is a feature of primary myelofibrosis

A multivariable analysis of 164 JAK2 V617F-positive myeloproliferative neoplasm patients

Brady L. Stein, Donna M. Williams, Ophelia Rogers, Mary Ann Isaacs, Jerry L Spivak, Alison R Moliterno

Research output: Contribution to journalArticle

Abstract

Objective: Suppression of normal hematopoiesis by the neoplastic clone (clonal dominance) is a feature of the myeloproliferative neoplasms, but the determinants that predict clonal dominance are unknown. The objective of this study was to identify clinical and laboratory variables that associate with the JAK2 V617F CD34+ progenitor allele burden and clonal dominance, which was defined by congruence of the JAK2 V617F CD34+ progenitor and neutrophil allele burdens. Materials and Methods: A cross-sectional analysis was performed on 164 consecutive JAK2 V617F-positive patients: 30 with essential thrombocytosis (ET), 100 with polycythemia vera (PV), and 34 with myelofibrosis (MF), including 8 post-ET MF and 3 post-PV MF. The JAK2 V617F CD34+ progenitor and neutrophil allele burdens were measured using an allele-specific, quantitative real-time polymerase chain reaction assay. Results: After adjusting for genotype, sex, age at diagnosis, and disease duration, disease type was the strongest predictor of clonal dominance, with the odds ratio being nearly 61.9 times higher for MF patients when compared with ET patients (p <0.001), and 9.7 times higher when compared with PV patients (p = 0.002). Additionally, clonal dominance was associated with a clinical phenotype of an increased spleen size (p = 0.006), increased white blood cell count (p = 0.009), and lower hemoglobin (p <0.001), even after adjusting for disease type and duration. Conclusions: These data indicate that loss of wild-type clones at the progenitor level is a feature of MF (primary MF, post-ET MF, and post-PV MF), presumably due to expansion of the JAK2 V617F clone and that this characteristic is surprisingly independent of JAK2 V617F homozygosity, suggesting that additional genomic lesions may contribute to this unique molecular process that distinguishes MF from ET and PV.

Original languageEnglish (US)
Pages (from-to)95-101
Number of pages7
JournalExperimental Hematology
Volume39
Issue number1
DOIs
StatePublished - Jan 2011

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Primary Myelofibrosis
Thrombocytosis
Polycythemia Vera
Neoplasms
Alleles
Neutrophils
Hematopoiesis
Leukocyte Count
Real-Time Polymerase Chain Reaction
Hemoglobins
Spleen
Clone Cells
Cross-Sectional Studies
Odds Ratio
Genotype
Phenotype

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Genetics
  • Molecular Biology
  • Hematology

Cite this

Disease burden at the progenitor level is a feature of primary myelofibrosis : A multivariable analysis of 164 JAK2 V617F-positive myeloproliferative neoplasm patients. / Stein, Brady L.; Williams, Donna M.; Rogers, Ophelia; Isaacs, Mary Ann; Spivak, Jerry L; Moliterno, Alison R.

In: Experimental Hematology, Vol. 39, No. 1, 01.2011, p. 95-101.

Research output: Contribution to journalArticle

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abstract = "Objective: Suppression of normal hematopoiesis by the neoplastic clone (clonal dominance) is a feature of the myeloproliferative neoplasms, but the determinants that predict clonal dominance are unknown. The objective of this study was to identify clinical and laboratory variables that associate with the JAK2 V617F CD34+ progenitor allele burden and clonal dominance, which was defined by congruence of the JAK2 V617F CD34+ progenitor and neutrophil allele burdens. Materials and Methods: A cross-sectional analysis was performed on 164 consecutive JAK2 V617F-positive patients: 30 with essential thrombocytosis (ET), 100 with polycythemia vera (PV), and 34 with myelofibrosis (MF), including 8 post-ET MF and 3 post-PV MF. The JAK2 V617F CD34+ progenitor and neutrophil allele burdens were measured using an allele-specific, quantitative real-time polymerase chain reaction assay. Results: After adjusting for genotype, sex, age at diagnosis, and disease duration, disease type was the strongest predictor of clonal dominance, with the odds ratio being nearly 61.9 times higher for MF patients when compared with ET patients (p <0.001), and 9.7 times higher when compared with PV patients (p = 0.002). Additionally, clonal dominance was associated with a clinical phenotype of an increased spleen size (p = 0.006), increased white blood cell count (p = 0.009), and lower hemoglobin (p <0.001), even after adjusting for disease type and duration. Conclusions: These data indicate that loss of wild-type clones at the progenitor level is a feature of MF (primary MF, post-ET MF, and post-PV MF), presumably due to expansion of the JAK2 V617F clone and that this characteristic is surprisingly independent of JAK2 V617F homozygosity, suggesting that additional genomic lesions may contribute to this unique molecular process that distinguishes MF from ET and PV.",
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