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

Abstract

Monocyte-derived fibrocytes recently garnered attention because 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 those in healthy controls (HCs). In this study, we evaluated SLAMF7high monocyte percentage in the PB of HCs, myeloproliferative neoplasm (MPN) patients with MF, and MPN patients without MF by using a cross-sectional approach. We found that MPN patients with MF who harbored JAK2V617F had a significantly elevated SLAMF7high monocyte percentage, which correlated positively with the JAK2V617F allele burden. In addition, the serum concentration of interleukin-1ra (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 useful noninvasive markers 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 derived not only from HCs but also 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 onset of MF in MPN patients harboring JAK2V617F, and Elo could be a therapeutic agent for MPN patients with MF who harbor JAK2V617F.

Reconstructing the lineage histories and differentiation trajectories of individual cancer cells inJAK2-mutant myeloproliferative neoplasms

“…6b). In particular, we found that SLAMF7, a cell surface marker previously shown to play a role in fibrocyte differentiation in myelofibrosis, was upregulated in JAK2-V617F CD14+ cells 35 . Thus, this population of cells could potentially be an early biomarker for risk of progression to myelofibrosis.…”

SLAMF7 engagement super-activates macrophages in acute and chronic inflammation

“…In the unstimulated state, SLAMF7 is expressed at high levels by plasma cells ( 35 ), and can also be expressed on B cells, T cells, and natural killer (NK) cells, but is expressed at low levels on resting macrophages ( 34 , 36 ). However, elevated SLAMF7 expression has been found on macrophages from atherosclerotic lesions ( 37 ) and from patients with myelofibrosis ( 38 ). BLIMP-1 regulates SLAMF7 expression in lymphocytes ( 39 ), but it is not well understood how this receptor is regulated in macrophages.…”

Novel Concepts of Treatment for Patients with Myelofibrosis and Related Neoplasms

“…Japanese investigators validated and extended this work to show that fibrocyte differentiation is triggered by myeloproliferative leukemia (MPL) receptor activation (by thrombopoietin) and that circulating monocytes highly expressing signaling lymphocytic activation molecule F7 (SLAMF7) were possible fibrocyte precursors [ 47 ]. They went on to show that particularly in JAK2 -mutated MF patients, the circulating SLAMF7 high monocyte percentage was significantly elevated, and correlated with JAK2 V617F allele burden [ 48 ]. While the former work from our group served as the basis for studying PRM-151 (recombinant pentraxin-2, or serum amyloid protein) in patients with MF (discussed below), the Japanese group identified the anti-SLAMF7 monoclonal antibody, elotuzumab, as a therapeutic candidate in MF.…”

“…While the former work from our group served as the basis for studying PRM-151 (recombinant pentraxin-2, or serum amyloid protein) in patients with MF (discussed below), the Japanese group identified the anti-SLAMF7 monoclonal antibody, elotuzumab, as a therapeutic candidate in MF. Elotuzumab inhibited fibrocyte differentiation in vitro and ameliorated bone marrow fibrosis and splenomegaly induced by romiplostim (thrombopoietin agonist) administration in humanized mice [ 48 ]. Accordingly, there are plans to study this agent in patients with JAK2 -mutated MF who are not candidates for JAK inhibitor therapy (NCT04517851).…”