The role of mast cells in bone marrow diseases

We read the article by Horny et al describing bone marrow mast cell (MC) specific protease expression patterns in cases of systemic mastocytosis and myelodysplastic syndromes (MDS) with great interest.¹ An increase in bone marrow MCs is a known feature of various haematological diseases, including myeloproliferative disorders and acquired severe aplastic anaemia (SAA). Although the MC increase is clonal in mastocytosis and benign in acquired SAA, its nature is not fully understood in myeloproliferative and myelodysplastic disorders.

Acquired SAA and hypoplastic MDS share several clinical and bone marrow features, and are often difficult to distinguish. Both conditions respond to immunosuppressive treatments. Is the increase in numbers of MCs in these conditions simply an innocent consequence of haemopoietic cell injury sparing MCs or, alternatively, does it contribute to the development of severe bone marrow hypoplasia/aplasia in return? MCs have long life spans and they probably are not directly affected by the attack against the stem cell compartment, resulting in relative MC increases in the bone marrow. Low to normal stem cell factor (SCF) values have been shown in SAA, unlike the increased concentrations of other haemopoietic growth factors.² This may be explained by greater dependency of MC survival and growth on SCF than other growth factors and by a negative feedback control mechanism in a population that is already supplied by an autocrine pathway. In support of this explanation, a reaction mimicking systemic mastocytosis was observed in a patient with aplastic anaemia who was treated with SCF, which was accompanied by a partial and transient haemopoietic recovery.³

MCs with various enzyme expression patterns may mediate different functions in certain tissues in which they exist. These patterns may also be related to the maturational stage of MCs. Nevertheless, the predominant MC type in certain tissues may be determined by the environmental needs. We think that the coexistence of chymase expressing MCs (MC_C) and chymase and tryptase expressing MCs in physiological conditions reflects a naturally occurring balance that contributes to tissue homeostasis. It is known that MCs can act as antigen presenters, in addition to being effector elements of the human immune system. Mast cells can kill target cells through the secretion of cytokines, such as tumour necrosis factor α and serine proteases, and potentially through direct cell to cell interactions. Granzyme H, one of the MC serine proteases, has chymase activity,⁴ and chymase is known to induce apoptosis in target cells.⁵ It has also been shown that the mast cell derived cell line P815 contains granzyme B RNA. In contrast, tryptase, another MC protease, is a well known mitogen that could induce growth of certain cells, such as airway smooth muscle cells, fibroblasts, and neuronal cells.⁶ Tryptase expressing MC (MC_T) are often found in tissue repair sites characterised by fibrosis.

The predominance of MC_T in systemic mastocytosis and patients with MDS was consistent with the typical presence of hypercellular marrow in these conditions.¹ Although the authors did not provide the number of cases with hypoplastic MDS in their series, the frequency is 5–10% in the adult literature, suggesting that most, if not all, of their cases had normocellular or hyperplastic MDS. The autocrine production of SCF with increased tryptase activity might have contributed to the extremely hypercellular bone marrow in those cases. The authors also described hypocellular bone marrow associated with a focal increase in MC with strong chymase expression in a case of indolent systemic mastocytosis, which suggests a possible MC_C contribution to hypocellularity. We recently showed an association between MC persistence and poor outcome in childhood SAA following immune suppression.⁷ In another study, we demonstrated longterm liquid culture grown human bone marrow MC cytotoxicity against human leukaemia cells.⁸ It is possible that those MCs had strong chymase expression. Regardless of the mechanisms involved, an increase in MCs, preferentially MC_C, may contribute to the hypocellularity seen in acquired SAA and hypoplastic MDS. This explanation is also consistent with the lack of fibrosis in acquired SAA and hypoplastic MDS, which could be secondary to specific MC_C increase.