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Tyk2 is dispensable for induction of myeloproliferative disease by mutant FLT3
Hideaki Nakajima1, Fumi Shibata, Hidetoshi Kumagai
1Center of Excellence, Institute of Medical Science, University of Tokyo, Tokyo, Japan. hnakajim@ims.u-tokyo.ac.jp.
Abstract:
Internal tandem duplication of FLT3 tyrosine kinase (FLT3-ITD) is the most prevalent mutation found in acute myelogenous leukemia (AML), having been identified in 20% to 30% of all AML patients. We have previously shown that FLT3-ITD signals mainly through the signal transducer and activator of transcription 5 (STAT5) pathway and have suggested the possible involvement of Tyk2 in STAT5 activation by FLT3-ITD. The present study addressed the role of Tyk2 in FLT3-ITD signaling in a murine bone marrow transplantation (BMT) model. Transplantation of wild-type bone marrow cells transduced with the FLT3-ITD gene induced lethal myeloproliferative disease (MPD) in the recipient mice at a median latency of 89 days. Interestingly, some mice presented the proliferation of B- or T-lymphoid blasts in various organs, a presentation that resembled acute lymphoblastic leukemia (ALL). Mice that received Tyk2-deficient bone marrow cells transduced with FLT3-ITD developed lethal MPD with a disease latency (median, 100 days) and pathologic picture similar to those of mice that received wild-type bone marrow cells. These results indicate that (1) Tyk2 is not essential for MPD induction by FLT3-ITD and (2) FLT3-ITD by itself can induce ALL in a murine BMT model.
Insights
FLT3-ITD mutations drive acute myelogenous leukemia (AML). This study found Tyrosine Kinase 2 (Tyk2) is not essential for FLT3-ITD induced myeloproliferative disease, and FLT3-ITD alone can cause acute lymphoblastic leukemia (ALL).
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- Internal tandem duplication of FLT3 tyrosine kinase (FLT3-ITD) is the most common mutation in acute myelogenous leukemia (AML), affecting 20-30% of patients.
- Previous research indicated FLT3-ITD signaling primarily involves the signal transducer and activator of transcription 5 (STAT5) pathway, with a potential role for Tyrosine Kinase 2 (Tyk2).
Purpose of the Study:
- To investigate the role of Tyk2 in FLT3-ITD signaling and its impact on disease development in a murine bone marrow transplantation (BMT) model.
- To determine if Tyk2 is essential for FLT3-ITD-induced myeloproliferative disease (MPD) and acute lymphoblastic leukemia (ALL).
Main Methods:
- Utilized a murine bone marrow transplantation (BMT) model.
- Transplanted wild-type and Tyk2-deficient bone marrow cells engineered to express the FLT3-ITD gene into recipient mice.
- Monitored disease latency, pathology, and blast proliferation.
Main Results:
- Transplantation of FLT3-ITD transduced wild-type bone marrow induced lethal MPD with a median latency of 89 days, and some mice developed ALL-like disease.
- Mice receiving Tyk2-deficient bone marrow transduced with FLT3-ITD also developed lethal MPD with a similar median latency (100 days) and pathology.
- These findings demonstrate that Tyk2 is not essential for FLT3-ITD-induced MPD.
Conclusions:
- Tyk2 is not essential for the induction of myeloproliferative disease by FLT3-ITD.
- FLT3-ITD mutation alone is capable of inducing acute lymphoblastic leukemia in this murine bone marrow transplantation model.
