Differential requirement for wild-type Flt3 in leukemia initiation among mouse models of human leukemia

Kenjiro Kamezaki, Larry L. Luchsinger, Hans Willem Snoeck

研究成果: ジャーナルへの寄稿記事

4 引用 (Scopus)

抄録

FLT3 is one of the most frequently mutated genes in acute leukemias. However, the role in leukemogenesis of wild-type (wt) FLT3, which is highly expressed in many hematologic malignancies, is unclear. We show here that in mouse models established by retroviral transduction of leukemic fusion proteins, deletion of Flt3 strongly inhibits MLL-ENL and to lesser extent p210BCR-ABL-induced leukemogenesis, but has no effect in MLL-AF9 or AML1-ETO9a models. Flt3 acts at the level of leukemic stem cells (LSCs), as a fraction of LSCs in MLL-ENL, but not in MLL-AF9-induced leukemia, expressed Flt3 in vivo, and Flt3 expression on LSCs was associated with leukemia development in this model. Furthermore, efficiency of MLL-ENL, but not of MLL-AF9-induced leukemia induction was significantly enhanced after transduction of Flt3+ compared to Flt3- wt myeloid progenitors. However, Flt3 is not required for immortalization of bone marrow cells in vitro by MLL-ENL and does not affect colony formation by MLL-ENL LSCs in vitro, suggesting that in vitro models do not reflect the in vivo biology of MLL-ENL leukemia with respect to Flt3 requirement. We conclude that wt Flt3 plays a role in leukemia initiation in vivo, which is, however, not universal.

元の言語英語
ページ(範囲)192-203.e1
ジャーナルExperimental Hematology
42
発行部数3
DOI
出版物ステータス出版済み - 1 1 2014
外部発表Yes

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Leukemia
Stem Cells
Hematologic Neoplasms
Bone Marrow Cells
Genes
In Vitro Techniques
Proteins

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Hematology
  • Genetics
  • Cell Biology
  • Cancer Research

これを引用

Differential requirement for wild-type Flt3 in leukemia initiation among mouse models of human leukemia. / Kamezaki, Kenjiro; Luchsinger, Larry L.; Snoeck, Hans Willem.

:: Experimental Hematology, 巻 42, 番号 3, 01.01.2014, p. 192-203.e1.

研究成果: ジャーナルへの寄稿記事

Kamezaki, Kenjiro ; Luchsinger, Larry L. ; Snoeck, Hans Willem. / Differential requirement for wild-type Flt3 in leukemia initiation among mouse models of human leukemia. :: Experimental Hematology. 2014 ; 巻 42, 番号 3. pp. 192-203.e1.
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abstract = "FLT3 is one of the most frequently mutated genes in acute leukemias. However, the role in leukemogenesis of wild-type (wt) FLT3, which is highly expressed in many hematologic malignancies, is unclear. We show here that in mouse models established by retroviral transduction of leukemic fusion proteins, deletion of Flt3 strongly inhibits MLL-ENL and to lesser extent p210BCR-ABL-induced leukemogenesis, but has no effect in MLL-AF9 or AML1-ETO9a models. Flt3 acts at the level of leukemic stem cells (LSCs), as a fraction of LSCs in MLL-ENL, but not in MLL-AF9-induced leukemia, expressed Flt3 in vivo, and Flt3 expression on LSCs was associated with leukemia development in this model. Furthermore, efficiency of MLL-ENL, but not of MLL-AF9-induced leukemia induction was significantly enhanced after transduction of Flt3+ compared to Flt3- wt myeloid progenitors. However, Flt3 is not required for immortalization of bone marrow cells in vitro by MLL-ENL and does not affect colony formation by MLL-ENL LSCs in vitro, suggesting that in vitro models do not reflect the in vivo biology of MLL-ENL leukemia with respect to Flt3 requirement. We conclude that wt Flt3 plays a role in leukemia initiation in vivo, which is, however, not universal.",
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