Activation of TRKB receptor in murine hematopoietic stem/progenitor cells induced mastocytosis

Yang, Min; Huang, Kezhi; Büsche, Guntram; Ganser, Arnold; Li, Zhixiong

doi:10.1182/blood-2014-03-560466

Cited by 8 publications

(22 citation statements)

References 10 publications

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“…MAPK in this study) that were present before the inhibitor therapy. Since NTs can be released by mast cells as well as bone marrow stromal cells, our data, together with our recent report demonstrating SM induction by BDNF-mediated activation of TRKB [ 19 ], suggest an important role of autocrine and/or paracrine activation of TRKs in the pathogenesis of mastocytosis. Moreover, we show a significantly prolonged survival of mice xenotransplanted with HMC-1 cells by targeting both TRK and KIT compared with targeting KIT alone.…”

Section: Discussionsupporting

confidence: 74%

“…In the TRKA/NGF group, four animals developed acute leukemia within 6 months after transplantation ( Supplementary Figure 1 ), while three animals developed SM within 12 months after transplantation. Consistent with SM induced by TRKB activation [ 19 ], abnormal mast cells mainly showed features of mature hypergranular mast cells (Figure 1B–1D ) [ 20 ]. These cells expressed CD25 , tryptase , KIT , and TRKA (Figure 1 , Supplementary Figure 2 ).…”

Section: Resultssupporting

confidence: 55%

“…These data strongly suggest that activation of TRKA by NGF is important for the development of mastocytosis. Although the SM incidence by TRKA activation was lower than by TRKB activation (3/7 = 43% vs. 12/17 = 71% [ 19 ]), our data indicate that activation of both TRKA and TRKB by their ligands are more potent than KIT D816V for induction of SM [ 19 ], since SM was not induced by retroviral-mediated expression of KIT D816V in similar settings [ 22 ]. Furthermore, only 29% of transgenic mice expressing human KIT D816V developed mastocytosis at an old age (> 12 months) [ 23 ].…”

Section: Resultsmentioning

confidence: 93%

“…In our historic controls of > 100 animals transplanted in similar settings with different genes, e.g. dTRKA, dLNGFR, FLT3 mutants, tCD34, and SV40 LT, no animals developed SM [ 19 , 21 ]. These data strongly suggest that activation of TRKA by NGF is important for the development of mastocytosis.…”

Section: Resultsmentioning

confidence: 99%

“…Our group has recently reported a potential role of TRK signaling in leukemogenesis [ 12 , 18 ]. More recently, we reported mastocytosis induced by activation of TRKB in murine hematopoietic stem/progenitor cells in vivo [ 19 ]. In this study, we demonstrate that activation of TRKA by its ligand NGF is also potent to elicit a disease with striking similarities to human SM in a mouse model and is involved in the development of resistance to KIT-targeted therapy.…”

Section: Introductionmentioning

confidence: 99%

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Activation of TRKA receptor elicits mastocytosis in mice and is involved in the development of resistance to KIT-targeted therapy

et al. 2017

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The neurotrophins (NTs) play a key role in neuronal survival and maintenance. The TRK (tropomyosin-related kinase) tyrosine kinase receptors (TRKA, TRKB, TRKC) are high affinity receptors for NTs. There is increasing data demonstrating an important role of the TRK family in cancer initiation and progression. NTs have been known for many years to promote chemotaxis, maturation, and survival of mast cells. However, the role of NT signaling in the pathogenesis of mastocytosis is not well understood. In this study, we demonstrate that activation of TRKA by its ligand nerve growth factor (NGF) is potent to trigger a disease in mice with striking similarities to human systemic mastocytosis (SM). Moreover, activation of TRKA by NGF strongly rescues KIT inhibition-induced cell death of mast cell lines and primary mast cells from patients with SM, and this rescue effect can be efficiently blocked by entrectinib (a new pan TRK specific inhibitor). HMC-1 mast cell leukemia cells that are resistant to KIT inhibition induced by TRKA activation show reactivation of MAPK/ERK (extracellular signal-regulated kinase) and strong upregulation of early growth response 3 (EGR3), suggesting an important role of MAPK-EGR3 axis in the development of resistance to KIT inhibition. Targeting both TRK and KIT significantly prolongs survival of mice xenotransplanted with HMC-1 cells compared with targeting KIT alone. Thus, these data strongly suggest that TRKA signaling can improve neoplastic mast cell fitness. This might explain at least in part why treatment with KIT inhibitors alone so far has been disappointing in most published clinical trials for mastocytosis. Our data suggest that targeting both KIT and TRKs might improve efficacy of molecular therapy in SM with KIT mutations.

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Section: Discussionsupporting

confidence: 74%

Section: Resultssupporting

confidence: 55%

Section: Resultsmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Activation of TRKA receptor elicits mastocytosis in mice and is involved in the development of resistance to KIT-targeted therapy

et al. 2017

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Leukemogenic potency of the novel FLT3-N676K mutant

et al. 2016

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The novel FMS-like tyrosine kinase 3 (FLT3)-N676K point mutation within the FLT3 kinase domain-1 was recently identified in 6 % of de novo acute myeloid leukemia (AML) patients with inv(16). Because FLT3-N676K was encountered almost exclusively in inv(16) AML, we investigated the transforming potential of FLT3-N676K, the cooperation between FLT3-N676K and core binding factor ß-smooth muscle myosin heavy chain (CBFß-SMMHC) (encoded by the inv(16) chimeric gene CBFB-MYH11) in inducing acute leukemia, and tested the sensitivity of FLT3-N676K-positive leukemic cells to FLT3 inhibitors. Retroviral expression of FLT3-N676K in myeloid 32D cells induced AML in syngeneic C3H/HeJ mice (n = 11/13, median latency 58 days), with a transforming activity similar to FLT3-internal tandem duplication (ITD) (n = 8/8), FLT3-TKD D835Y (n = 8/9), and FLT3-ITD-N676K (n = 9/9) mutations. Three out of 14 (21.4 %) C57BL/6J mice transplanted with FLT3-N676K-transduced primary hematopoietic progenitor cells developed acute leukemia (latency of 68, 77, and 273 days), while no hematological malignancy was observed in the control groups including FLT3-ITD. Moreover, co-expression of FLT3-N676K/CBFß-SMMHC did not promote acute leukemia in three independent experiments (n = 16). In comparison with FLT3-ITD, FLT3-N676K induced much higher activation of FLT3 and tended to trigger stronger phosphorylation of MAPK and AKT. Importantly, leukemic cells carrying the FLT3-N676K mutant in the absence of an ITD mutation were highly sensitive to FLT3 inhibitors AC220 and crenolanib, and crenolanib even retained activity against the AC220-resistant FLT3-ITD-N676K mutant. Taken together, the FLT3-N676K mutant is potent to transform murine hematopoietic stem/progenitor cells in vivo. This is the first report of acute leukemia induced by an activating FLT3 mutation in C57BL/6J mice. Moreover, further experiments investigating molecular mechanisms for leukemogenesis induced by FLT3-N676K mutation and clinical evaluation of FLT3 inhibitors in FLT3-N676K-positive AML seem warranted.

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Neurotrophin Signaling and Stem Cells—Implications for Neurodegenerative Diseases and Stem Cell Therapy

2016

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Neurotrophins (NTs) are members of a neuronal growth factor protein family whose action is mediated by the tropomyosin receptor kinase (TRK) receptor family receptors and the p75 NT receptor (p75NTR), a member of the tumor necrosis factor (TNF) receptor family. Although NTs were first discovered in neurons, recent studies have suggested that NTs and their receptors are expressed in various types of stem cells mediating pivotal signaling events in stem cell biology. The concept of stem cell therapy has already attracted much attention as a potential strategy for the treatment of neurodegenerative diseases (NDs). Strikingly, NTs, proNTs, and their receptors are gaining interest as key regulators of stem cells differentiation, survival, self-renewal, plasticity, and migration. In this review, we elaborate the recent progress in understanding of NTs and their action on various stem cells. First, we provide current knowledge of NTs, proNTs, and their receptor isoforms and signaling pathways. Subsequently, we describe recent advances in the understanding of NT activities in various stem cells and their role in NDs, particularly Alzheimer's disease (AD) and Parkinson's disease (PD). Finally, we compile the implications of NTs and stem cells from a clinical perspective and discuss the challenges with regard to transplantation therapy for treatment of AD and PD.

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Activation of TRKB receptor in murine hematopoietic stem/progenitor cells induced mastocytosis

Cited by 8 publications

References 10 publications

Activation of TRKA receptor elicits mastocytosis in mice and is involved in the development of resistance to KIT-targeted therapy

Activation of TRKA receptor elicits mastocytosis in mice and is involved in the development of resistance to KIT-targeted therapy

Leukemogenic potency of the novel FLT3-N676K mutant

Neurotrophin Signaling and Stem Cells—Implications for Neurodegenerative Diseases and Stem Cell Therapy

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