Mutations in JAK2 and Calreticulin genes are associated with specific alterations of the immune system in myelofibrosis

Abstract

Myelofibrosis (MF) is a clonal neoplasia associated with chronic inflammation due to aberrant cytokine production. Mutations in Janus Kinase-2 (JAK2), calreticulin (CALR) and myeloproliferative leukemia protein (MPL) genes have been recently associated to MF and they all activate the JAK/STAT signaling pathway. Since this pathway is essential in shaping the immune response, we investigated the role of circulating immune subsets and cytokines in 38 patients (20 carrying JAK2,13 exon-9 CALR mutation and 5 triple negative). In comparison to healthy donors, patients presented a reduced amount of circulating dendritic cells (DCs) associated with a defective ability of monocytes in differentiating into DCs. In addition, we found a reduction in circulating T-helper (Th)1 and Th17 and hypo-functional innate lymphoid cells (ILC). Results analyzed according to the mutational status showed that patients carrying JAK2 mutation had a reduction in Th17, myeloid-DCs and effector Tregs as well as increased ILC1 and cytokine producing Tregs. The CALR mutated patients revealed high ILC3 levels, reduced Th1 and their monocytes had a reduced capacity to mature into fully committed DCs. Their Tregs were also less effective in inhibiting the proliferation of autologous effector T-cells due to an increased proliferative status induced by CALR mutation. Triple negative patients presented a reduced amount of total circulating CD3, effectors Tregs and Th1 with increased ILC1. Overall, we have demonstrated that in MF different mutations lead to phenotypic and functional alterations in different immune subsets that may have a potential role in disease progression and susceptibility to infections.

Epidemiology, outcome, and risk factors for infectious complications in myelofibrosis patients receiving ruxolitinib: A multicenter study on 446 patients

“…Indeed, several immune abnormalities have been observed in MF patients: lymphopenia with decreased cytotoxic T cells, increased abnormal macrophages, elevated myeloid‐derived suppressor cells, and lower T‐regulatory cells . Very recently, we demonstrated that mutation status correlates with specific immune alterations in MF …”

The role of circulating monocytes and JAK inhibition in the infectious-driven inflammatory response of myelofibrosis

“…Here we have shown that MF monocytes exhibit phenotypic and functional alterations that may contribute to the increased susceptibility to infections in MF. Furthermore, in our previous study, 21 we demonstrated that MF monocytes failed to fully differentiate in DCs showing a macrophage-like phenotype. This finding was supported by a reduced amount of circulating myeloid and plasmacytoid DCs.…”

“…[10][11][12][13] Specifically, numerical and/or functional abnormalities were documented in the monocyte/macrophage compartment, T-cells, natural killer, and myeloid-derived suppressor cells. 10,[14][15][16][17][18][19][20][21] We previously demonstrated that in MF there is a reduced ability of monocytes to differentiate into dendritic cells, decreased plasticity of Th17 lymphocytes and functionally impaired Innate Lymphoid Cells. 21 To further aggravate the clinical landscape, prior studies have demonstrated significant inhibitory effects in T cells, natural killer and dendritic cells function after exposure to JAK inhibitors.…”

“…10,[14][15][16][17][18][19][20][21] We previously demonstrated that in MF there is a reduced ability of monocytes to differentiate into dendritic cells, decreased plasticity of Th17 lymphocytes and functionally impaired Innate Lymphoid Cells. 21 To further aggravate the clinical landscape, prior studies have demonstrated significant inhibitory effects in T cells, natural killer and dendritic cells function after exposure to JAK inhibitors. [22][23][24][25][26][27] Therapy with Ruxolitinib (RUX), a JAK1/2 inhibitor, suppresses clonal myeloproliferation and release of proinflammatory cytokines, reducing splenomegaly and constitutional symptoms in around 50% of MF patients.…”

<p>Tuberculosis in Patients with Primary Myelofibrosis During Ruxolitinib Therapy: Case Series and Literature Review</p>

“…Published works demonstrate that the count of regulatory T cells has decreased before the introduction of rux, which may contribute to a pro-inflammatory status and disrupt the immune surveillance of myelofibrosis (MF) patients. 5,6…”