Increased B cell activation is present in JAK2V617F-mutated, CALR-mutated and triple-negative essential thrombocythemia

Abstract

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.

Non-canonical Hedgehog signaling mediates profibrotic hematopoiesis-stroma crosstalk in myeloproliferative neoplasms

“…Altered lymphocyte levels in patients with MPNs have been reported previously 19 , 20 and were confirmed in our cohort ( Figures S1 D and S1E). In our cohort, GLI1 levels in T cells were significantly correlated with onset of fibrosis, and the same trend was seen in the B cell population ( Figure 1 F).…”

Non-Canonical Hedgehog Signaling Mediates Profibrotic Hematopoiesis-Stroma Crosstalk in Myeloproliferative Neoplasms

“…Altered lymphocyte levels in patients with MPNs have been reported previously 19,20 and were confirmed in our cohort (Figures S1D and S1E). In our cohort, GLI1 levels in T cells were significantly correlated with onset of fibrosis, and the same trend was seen in the B cell population (Figure 1F).…”

Lymphoproliferative disorders in patients with chronic myeloproliferative neoplasms: A systematic review

“…Moreover, the mutation has been reported in peripheral lymphocytes of PV patients and in some LPD incurring in JAK2 mutated MPN . Furthermore, most recently, JAK2V617F mutated ET patients showed a significantly higher fraction of activated B cells as compared with healthy adults and triple‐negative ET . Finally, the rs2736100_C TERT variant increased the risk of solid cancers more profoundly in JAK2 mutated patients, due to a possible synergic action.…”