Impact of gene dosage, loss of wild-type allele, and FLT3 ligand on Flt3-ITD-induced myeloproliferation

Shabnam Kharazi, Adam J. Mead, Anna Mansour, Anne Hultquist, Charlotta Böiers, Sidinh Luc, Natalija Buza-Vidas, Zhi Ma, Helen Ferry, Debbie Atkinson, Kristian Reckzeh, Kristina Masson, Jörg Cammenga, Lars Rönnstrand, Fumio Arai, Toshio Suda, Claus Nerlov, Ewa Sitnicka, Sten Eirik W Jacobsen

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Acquisition of homozygous activating growth factor receptor mutations might accelerate cancer progression through a simple gene-dosage effect. Internal tandem duplications (ITDs) of FLT3 occur in approximately 25% cases of acute myeloid leukemia and induce ligand-independent constitutive signaling. Homozygous FLT3-ITDs confer an adverse prognosis and are frequently detected at relapse. Using a mouse knockin model of Flt3 - internal tandem duplication (Flt3-ITD) - induced myeloproliferation, we herein demonstrate that the enhanced myeloid phenotype and expansion of granulocyte-monocyte and primitive Lin -Sca1 +c-Kit + progenitors in Flt3-ITD homozygous mice can in part be mediated through the loss of the second wild-type allele. Further, whereas autocrine FLT3 ligand production has been implicated in FLT3-ITD myeloid malignancies and resistance to FLT3 inhibitors, we demonstrate here that the mouse Flt3 ITD/ITD myeloid phenotype is FLT3 ligand-independent.

Original languageEnglish
Pages (from-to)3613-3621
Number of pages9
JournalBlood
Volume118
Issue number13
DOIs
Publication statusPublished - 2011 Sep 29

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Gene Dosage
Genes
Alleles
Ligands
Phenotype
Growth Factor Receptors
Granulocytes
Acute Myeloid Leukemia
Monocytes
Neoplasms
Recurrence
Mutation
flt3 ligand protein

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Kharazi, S., Mead, A. J., Mansour, A., Hultquist, A., Böiers, C., Luc, S., ... Jacobsen, S. E. W. (2011). Impact of gene dosage, loss of wild-type allele, and FLT3 ligand on Flt3-ITD-induced myeloproliferation. Blood, 118(13), 3613-3621. https://doi.org/10.1182/blood-2010-06-289207

Impact of gene dosage, loss of wild-type allele, and FLT3 ligand on Flt3-ITD-induced myeloproliferation. / Kharazi, Shabnam; Mead, Adam J.; Mansour, Anna; Hultquist, Anne; Böiers, Charlotta; Luc, Sidinh; Buza-Vidas, Natalija; Ma, Zhi; Ferry, Helen; Atkinson, Debbie; Reckzeh, Kristian; Masson, Kristina; Cammenga, Jörg; Rönnstrand, Lars; Arai, Fumio; Suda, Toshio; Nerlov, Claus; Sitnicka, Ewa; Jacobsen, Sten Eirik W.

In: Blood, Vol. 118, No. 13, 29.09.2011, p. 3613-3621.

Research output: Contribution to journalArticle

Kharazi, S, Mead, AJ, Mansour, A, Hultquist, A, Böiers, C, Luc, S, Buza-Vidas, N, Ma, Z, Ferry, H, Atkinson, D, Reckzeh, K, Masson, K, Cammenga, J, Rönnstrand, L, Arai, F, Suda, T, Nerlov, C, Sitnicka, E & Jacobsen, SEW 2011, 'Impact of gene dosage, loss of wild-type allele, and FLT3 ligand on Flt3-ITD-induced myeloproliferation', Blood, vol. 118, no. 13, pp. 3613-3621. https://doi.org/10.1182/blood-2010-06-289207
Kharazi S, Mead AJ, Mansour A, Hultquist A, Böiers C, Luc S et al. Impact of gene dosage, loss of wild-type allele, and FLT3 ligand on Flt3-ITD-induced myeloproliferation. Blood. 2011 Sep 29;118(13):3613-3621. https://doi.org/10.1182/blood-2010-06-289207
Kharazi, Shabnam ; Mead, Adam J. ; Mansour, Anna ; Hultquist, Anne ; Böiers, Charlotta ; Luc, Sidinh ; Buza-Vidas, Natalija ; Ma, Zhi ; Ferry, Helen ; Atkinson, Debbie ; Reckzeh, Kristian ; Masson, Kristina ; Cammenga, Jörg ; Rönnstrand, Lars ; Arai, Fumio ; Suda, Toshio ; Nerlov, Claus ; Sitnicka, Ewa ; Jacobsen, Sten Eirik W. / Impact of gene dosage, loss of wild-type allele, and FLT3 ligand on Flt3-ITD-induced myeloproliferation. In: Blood. 2011 ; Vol. 118, No. 13. pp. 3613-3621.
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