Increased B cell activation is present in JAK2V617F-mutated, CALR-mutated and triple-negative essential thrombocythemia
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Ken-Hong Lim1,2,3,4, Caleb Gon-Shen Chen2,3,4,5, Yu-Cheng Chang2,3,4, Yi-Hao Chiang2,3, Chen-Wei Kao3, Wei-Ting Wang3, Chiao-Yi Chang3, Ling Huang3, Ching-Sung Lin3, Chun-Chia Cheng3, Hung-I Cheng6, Nai-Wen Su2,3,4, Johnson Lin2, Yi-Fang Chang2,3,4, Ming-Chih Chang2,3,4, Ruey-Kuen Hsieh2,3, Huan-Chau Lin2,3 and Yuan-Yeh Kuo1
1 Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan
2 Department of Internal Medicine, Division of Hematology and Oncology, MacKay Memorial Hospital, Taipei, Taiwan
3 Department of Medical Research, Laboratory of Good Clinical Research Center, MacKay Memorial Hospital, Tamsui District, New Taipei City, Taiwan
4 Department of Medicine, MacKay Medical College, New Taipei City, Taiwan
5 Institute of Molecular and Cellular Biology, National Tsing-Hua University, Hsinchu, Taiwan
6 Department of Internal Medicine, Division of Hematology and Oncology, MacKay Memorial Hospital, Hsinchu, Taiwan
Ken-Hong Lim, email:
Huan-Chau Lin, email:
Yuan-Yeh Kuo, email:
Keywords: B cell, CALR, essential thrombocythemia, immune
Received: January 06, 2017 Accepted: February 28, 2017 Published: March 18, 2017
Essential thrombocythemia (ET) is a BCL-ABL1-negative myeloproliferative neoplasm. We have reported that increased activated B cells can facilitate platelet production mediated by cytokines regardless JAK2 mutational status in ET. Recently, calreticulin (CALR) mutations were discovered in ~30% JAK2/MPL-unmutated ET and primary myelofibrosis. Here we sought to screen for CALR mutations and to evaluate B cell immune profiles in a cohort of adult Taiwanese ET patients. B cell populations, granulocytes/monocytes membrane-bound B cell-activating factor (mBAFF) levels, B cells toll-like receptor 4 (TLR4) expression and intracellular levels of interleukin (IL)-1β/IL-6 and the expression of CD69, CD80, and CD86 were quantified by flow cytometry. Serum BAFF concentration was measured by ELISA. 48 healthy adults were used for comparison. 19 (35.2%) of 54 ET patients harbored 8 types of CALR exon 9 mutations including 4 (7.4%) patients with concomitant JAK2V617F mutations. Compared to JAK2V617F mutation, CALR mutations correlated with younger age at diagnosis (p=0.04), higher platelet count (p=0.004), lower hemoglobin level (p=0.013) and lower leukocyte count (p=0.013). Multivariate analysis adjusted for age, sex, follow-up period and hematological parameters confirmed that increased activated B cells were universally present in JAK2-mutated, CALR-mutated and triple-negative ET patients when compared to healthy adults. JAK2- and CALR-mutated ET have significantly higher fraction of B cells with TLR4 expression when compared to triple-negative ET (p=0.019 and 0.02, respectively). CALR-mutated ET had significantly higher number of CD69-positive activated B cells when compared to triple-negative ET (p=0.035). In conclusion, increased B cell activation is present in ET patients across different mutational subgroups.
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