To the editor:
Dysregulation of tropomyosin-related kinase (TRK) receptors has been reported to be involved in many human diseases, including cancer and neurological diseases. Recently, Peng et al1 demonstrated that patients with mastocytosis had enhanced neurotrophin levels and elevated expression of TRK receptors on skin and gut mast cells, suggesting that TRK signaling might contribute to the pathogenesis of mastocytosis by autocrine and paracrine loops. We recently demonstrated a potential role of neurotrophins and TRK signaling in leukemia development.2⇓-4 Overexpression of TRKB and its ligand brain-derived neurotrophic factor (BDNF) could transform murine primary hematopoietic stem/progenitor cells.4 Now we demonstrate that activation of TRKB by BDNF in murine hematopoietic stem/progenitor cells also efficiently induces a disease with striking similarities to human systemic mastocytosis (SM) in vivo.
To investigate the role of TRKB signaling in leukemogenesis, 37 C57BL/6J mice were transplanted with retrovirally gene-modified primary hematopoietic stem/progenitor cells (TRKB/BDNF = 17, TRKB = 8, BDNF = 5, tCD34 = 7) in 3 independent experiments (some data from the first experiment were recently published4). The experiments were terminated after an observation time of up to 454 days (mean 354 days). Interestingly, lymphoblastic leukemia was diagnosed in 5 animals (supplemental Data; available on the Blood Web site), whereas the other 12 animals with coexpression of TRKB/BDNF unexpectedly developed SM, affecting mainly spleen, liver, and bone marrow (see figure panels A-F) with multifocal compact mast cell infiltrates. Mast cells demonstrated mainly features of mature hypergranular mast cells (Figure 1E),5 expressing TRKB, BDNF, c-Kit, tryptase, and high affinity receptors for IgE (FcεRI) and CD25 (Figure 1G-H,J; supplemental Figure 1). Most SM animals followed an indolent course, and none of the animals became moribund or died before termination of the experiments. In contrast, leukemic mice survived <6 months after transplantation. At the final analysis, most of the SM animals had normal blood counts; only 2 animals showed slight enlargement of spleen. There was no evidence of classical mast cell leukemia6 or other hematological neoplasm in animals with SM. Moreover, no mutations in the c-Kit gene were detectable in any of the analyzed SM mice with high mast cell burden (n = 4). In contrast to TRKB/BDNF, no animals with TRKB alone, BDNF alone, or tCD34 showed mastocytosis or other hematological malignancies (supplemental Figure 2) except 1 TRKB mouse, which had slightly increased numbers of mastocytes (not fulfilling the criteria for SM) (supplemental Figure 3), probably due to mild activation of TRKB by its overexpression. In historic controls of >60 animals transplanted in a similar setting with different genes, eg, EGFP, tCD34, dLNGFR, and SV40 LT, no animals demonstrated SM. These data strongly suggest that activation of TRKB by BDNF (autocrine or paracrine; Figure 1G) is important to promote mastocytosis. Interestingly, TRKB activation in our model efficiently induced SM (incidence: 12/17 = 71%), whereas KIT D816V transgenic mice demonstrated a lower incidence of SM (8/28 = 29%).7 Furthermore, retroviral-mediated expression of KIT D816V even failed to induce SM in transplanted animals.8
Interestingly, in contrast to transplantation with primary hematopoietic stem/ progenitor cells, C3H/HeJ animals (n = 5 in 2 independent experiments, including the recently published experiment4) transplanted with TRKB and BDNF modified 32D cells (murine myeloid progenitors) developed only myeloid leukemia with no sign of increased mastocyte numbers. The fact that mastocytosis is induced only when TRKB is activated in hematopoietic stem/progenitor cells strongly supports the accepted view that mast cells are derived from hematopoietic stem cells.9
In summary, we provide the first direct evidence for induction of mastocytosis by activation of TRKB in hematopoietic stem/progenitor cells in vivo. Our data strongly support the findings by Peng et al1 and their hypothesis and indicate an important role of TRKB in the pathogenesis of mastocytosis.
Acknowledgments: This work was supported by the Deutsche Forschungsgemeinschaft (grant Li 1608/2-1) and the Deutsche Krebshilfe (grant 108245). K.H. was supported by the China Scholarship Council (2011638024).
Contribution: M.Y. performed research, collected, analyzed, and interpreted data, and wrote the manuscript; K.H. performed research; G.B. performed histological analysis; A.G. performed cytological analysis and revised the manuscript; and Z.L. conceived the concept, performed research, collected, analyzed and interpreted data, and wrote the manuscript.
Conflict-of-interest disclosure: The authors declare no competing financial interests.
Correspondence: Zhixiong Li, Institute of Experimental Hematology, OE6960, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany; e-mail:.
A.G. and Z.L. are cosenior authors.
The online version contains a data supplement.
- © 2014 by The American Society of Hematology