Systemic mastocytosis: dying or survivin

In this issue of Blood, Greiner et al¹ demonstrate that aberrant mast cells in systemic mastocytosis with the KIT D816V mutation release tumor necrosis factor (TNF), which gives the cells a growth advantage, compared with nonmutated myeloid cells, and worsens the clinical outcome for the patients (see figure).

Systemic mastocytosis is a heterogeneous mast cell disease, where most of the patients have a D816V mutation in KIT, the receptor for stem cell factor, causing receptor autoactivation. The majority of the patients have an indolent form of the disease, suffering from mast cell mediator symptoms from various organs, whereas advanced forms of systemic mastocytosis have a much worse prognosis.² The KIT D816V mutation affects many important functions in mast cells; besides growth advantages and improved survival, the mutant cells also exhibit increased migration and enhanced cytokine production and release. At least some of the cytokines that are elevated in systemic mastocytosis are driven by the KIT D816V mutation. An example is interleukin-6 (IL-6),³ and the serum level of IL-6 is associated with risk of disease progression.⁴ However, the insights into how the altered cytokine production affects disease have remained limited. A deregulated cytokine production could potentially affect the mast cells themselves, disturb hematopoiesis, and/or have systemic effects on other cell types and organs, leading to some of the symptoms related to systemic mastocytosis. Thus, deciphering the contribution of different cytokines to the pathophysiology of systemic mastocytosis can shed light on the disease mechanisms and has potential to identify new drug targets. Here, we discuss the results from Greiner et al and highlight how the neoplastic mast cells transform their microenvironment to promote their own dominance.

Greiner et al identified that patients with systemic mastocytosis display elevated serum levels of TNF. By comparing mast cells with and without the KIT D816V mutation, the study shows that the presence of the KIT D816V mutation results in dramatically increased TNF production. These results demonstrate that KIT D816V mutant mast cells constitute a possible source of the elevated TNF levels observed in the patients. More importantly, they showed that TNF can suppress myelopoiesis and the proliferation of mast cells without the KIT D816V mutation. By contrast, TNF has no effects on the proliferation of KIT D816V mutant mast cells. Thus, the neoplastic clone has the potential to promote its dominance over nonmutated mast cells through TNF production—an advantage beyond the cell-intrinsic effects of bypassing stem cell factor binding to stimulate cell proliferation and survival. Translated into the clinical setting, KIT D816V mutant mast cells are likely promoting a TNF-rich microenvironment in which only the neoplastic clone thrives and the growth of normal mast cells is suppressed. Over time, this would result in the complete takeover of mutant mast cells in the patients.

That elevated TNF levels promote a neoplastic clone has been reported in myeloproliferative neoplasms⁵ and juvenile myelomonocytic leukemia.⁶ In myeloproliferative neoplasms, the JAK2 V617F mutation promotes TNF production while conferring resistance to the myelopoiesis-suppressing effects of TNF. In juvenile myelomonocytic leukemia, not only is the neoplastic monocyte clone resistant to the high TNF levels, but TNF also stimulates the neoplastic monocytes’ growth. In Greiner et al, the tryptase levels (as proxy of mast cell burden) in systemic mastocytosis correlated weakly with the systemic TNF levels, which indicates that cells other than mature mast cells contribute to the TNF-rich microenvironment that promotes the neoplastic mast cell dominance. One possibility is that the acquisition of the KIT D816V mutation results in gained TNF-producing capacity also in a non–mast cell population and that these cells contribute to the TNF production in disease. The hematopoietic progenitor cell population expresses KIT and harbors the KIT D816V mutation in various patients with systemic mastocytosis⁷ and could potentially contribute to the increased TNF levels and worse outcome. However, the lack of correlation between KIT D816V mutation burden and TNF levels is difficult to interpret in this context. An alternative scenario is that nonmutated monocytes gain potential to produce excessive amounts of TNF in the atypical disease setting,⁸ thereby contributing to the mutated mast cell expansion and worse disease outcome.

The molecular mechanisms behind the KIT D816V mutant mast cells’ resistance to TNF is possibly attributed to the BIRC5 gene, coding for the antiapoptotic protein survivin. Mast cells that harbor the KIT D816V mutation upregulate survivin following TNF treatment, and the knockdown of BIRC5 in the cells results in impaired cell proliferation. Together, the results hint that the KIT D816V mutation confers resistance to TNF via survivin. However, it is important to point out that the DepMap consortium classifies BIRC5 as a common essential gene in (cancer) cell lines, that is, virtually all screened cell lines die or stop proliferating following BIRC5 disruption.⁹ Further experimental evidence is therefore warranted to verify whether the KIT D816V mutation establishes a survivin-mediated TNF resistance pathway.

Although the TNF-related mechanisms that promote neoplasia are not entirely new for the broader cancer research community, they represent a significant step toward understanding systemic mastocytosis on the cellular, molecular, and patient levels (see figure). Elevated levels of TNF in serum appear to be a commonality among patients with systemic mastocytosis, regardless of whether the disease is of indolent or advanced nature, when compared with healthy individuals. Interestingly, a subset of these patients displays higher TNF levels, coinciding with diminished survival. It is presently unclear whether and how TNF-targeting therapies would benefit these patients, but such an approach may present one of many tools to evaluate in the precision medicine era.

Conflict-of-interest disclosure: The authors declare no competing financial interests.