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

Kenjiro Kamezaki, Larry L. Luchsinger, Hans Willem Snoeck

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)192-203.e1
JournalExperimental Hematology
Volume42
Issue number3
DOIs
Publication statusPublished - Jan 1 2014
Externally publishedYes

Fingerprint

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

Cite this

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

In: Experimental Hematology, Vol. 42, No. 3, 01.01.2014, p. 192-203.e1.

Research output: Contribution to journalArticle

@article{20cdf03bea364d4a85c219ed2ccfdf7e,
title = "Differential requirement for wild-type Flt3 in leukemia initiation among mouse models of human leukemia",
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.",
author = "Kenjiro Kamezaki and Luchsinger, {Larry L.} and Snoeck, {Hans Willem}",
year = "2014",
month = "1",
day = "1",
doi = "10.1016/j.exphem.2013.11.008",
language = "English",
volume = "42",
pages = "192--203.e1",
journal = "Experimental Hematology",
issn = "0301-472X",
publisher = "Elsevier Inc.",
number = "3",

}

TY - JOUR

T1 - Differential requirement for wild-type Flt3 in leukemia initiation among mouse models of human leukemia

AU - Kamezaki, Kenjiro

AU - Luchsinger, Larry L.

AU - Snoeck, Hans Willem

PY - 2014/1/1

Y1 - 2014/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84897780344&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84897780344&partnerID=8YFLogxK

U2 - 10.1016/j.exphem.2013.11.008

DO - 10.1016/j.exphem.2013.11.008

M3 - Article

C2 - 24269847

AN - SCOPUS:84897780344

VL - 42

SP - 192-203.e1

JO - Experimental Hematology

JF - Experimental Hematology

SN - 0301-472X

IS - 3

ER -