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Increased SLAMF7high monocytes in myelofibrosis patients harboring JAK2V617F provide a therapeutic target of elotuzumab

Takaaki Maekawa, Shoichiro Kato, Toshikuni Kawamura, Kohei Takada, Takehiro Sone, Hiraku Ogata, Keita Saito, Takuya Izumi, Shigeki Nagao, Kosuke Takano, Yosuke Okada, Noriaki Tachi, Masahiro Teramoto, Toshikatsu Horiuchi, Reina Hikota-Saga, Kaori Endo-Umeda, Shigeyuki Uno, Yukiko Osawa, Ayako Kobayashi, Shinichi Kobayashi, Ken Sato, Michihiro Hashimoto, Shinya Suzu, Kensuke Usuki, Soji Morishita, Marito Araki, Makoto Makishima, Norio Komatsu and Fumihiko Kimura

Key Points

  • SLAMF7high CD16negative monocytes increased in peripheral blood of patients with myelofibrosis in correlation with JAK2V617F mutation.

  • Anti-SLAMF7 antibody suppressed monocyte-derived fibrocyte differentiation and could be a potent therapeutic agent for myelofibrosis.

Abstract

Monocyte-derived fibrocytes recently garnered attention as the novel pathogenesis of myelofibrosis (MF) and suppression of fibrocyte differentiation by serum amyloid P remarkably improved MF. We previously revealed that human fibrocytes highly expressed signaling lymphocytic activation molecule-F7 (SLAMF7) compared with macrophages and that SLAMF7high monocytes in the peripheral blood (PB) of MF patients were significantly elevated relative to healthy controls (HCs). In this study, we evaluated SLAMF7high monocyte percentage in PB of HCs, myeloproliferative neoplasm (MPN) patients without MF, and MPN patients with MF using a cross-sectional approach. We found that MPN patients harboring JAK2V617F with MF had a significantly elevated SLAMF7high monocyte percentage, which correlated positively with the JAK2V617F allele burden. Additionally, the serum concentration of IL-1ra was significantly correlated with the SLAMF7high monocyte percentage and JAK2V617F allele burden. These findings suggest that both SLAMF7high monocytes and IL-1ra could be a useful non-invasive marker of MF onset. Furthermore, the JAK2V617F allele burden of SLAMF7high monocytes was significantly higher than that of SLAMF7low monocytes and could be a potential target of elotuzumab (Elo), an anti-SLAMF7 antibody used for treating multiple myeloma. Elo independently inhibited differentiation of fibrocytes not only derived from HCs but also derived from MF patients in vitro. Elo also ameliorated MF and splenomegaly induced by romiplostim administration in humanized NOG mice. In conclusion, an increase of SLAMF7high monocytes with higher JAK2V617F allele burden was associated with the MF onset in MPN patients harboring JAK2V617F, and Elo could be a therapeutic agent for MPN patients harboring JAK2V617F with MF.

  • Submitted February 7, 2019.
  • Revision received July 2, 2019.
  • Accepted June 12, 2019.