FLT3 Mutations Confer Enhanced Proliferation and Survival Properties to Multipotent Progenitors in a Murine Model of Chronic Myelomonocytic Leukemia

Lee, Benjamin H.; Tóthová, Zuzana; Levine, Ross L.; Anderson, Kristina; Buza‐Vidas, Natalija; Cullen, Dana E.; McDowell, Elizabeth; Adelsperger, Jennifer; Fröhling, Stefan; Huntly, Brian J. P.; Beran, Miloslav; Jacobsen, Sten Eirik W.; Gilliland, D. Gary

doi:10.1016/j.ccr.2007.08.031

Cited by 185 publications

(230 citation statements)

References 52 publications

Supporting

Mentioning

208

Contrasting

Order By: Relevance

“…STAT5 is a direct target of FLT3 ITD 29 and activation of the STAT5 pathway by FLT3 ITD was previously shown. 14 In accordance with previous data, the FLT3 ITD-related activation of STAT5 is a strong proliferative signal and probably the cause of expansion of the MPP compartment. 14,30,31 However, addition of FLT3 ITD in KLI cohorts had no effect on myeloid gene expression.…”

Section: Resultssupporting

confidence: 91%

“…14 In accordance with previous data, the FLT3 ITD-related activation of STAT5 is a strong proliferative signal and probably the cause of expansion of the MPP compartment. 14,30,31 However, addition of FLT3 ITD in KLI cohorts had no effect on myeloid gene expression. Therefore, the higher frequency of myeloid progenitors can only be attributed to proliferative effect of FLT3 ITD.…”

Section: Resultssupporting

confidence: 91%

“…11,14,18 Briefly, insertion of a premature stop codon between the p42 and p30 C/EBPa start sites results in exclusive p30 C/EBPa translation (Cebpa Lp30 or L allele; Cebpa L/ þ ). The K313KK mutation was generated by insertion of an additional lysine in the C/EBPa coding sequence (Cebpa K313KK or K allele; Cebpa K/ þ ) leading to disruption of the basic region leucine zipper of C/EBPa.…”

Section: Mouse Strainsmentioning

confidence: 99%

“…12,13 Knockin mouse models have shown that FLT3 ITD causes suppression of lymphoid differentiation and increased proliferation of myeloid progenitors leading to a myeloproliferative phenotype without progression to AML. 14,15 Clinical data demonstrate CEBPA mutations as a reoccurring partner in AML with FLT3 ITD. 5,16,17 However, there is no study investigating FLT3 ITD in cooperation with CEBPA mutations where FLT3 ITD or both oncogenes are expressed from their own promoter at the original locus.…”

Section: Introductionmentioning

confidence: 99%

“…One strain contains an ITD mutation in the endogenous murine Flt3 locus, 14 which was cross-bred with a knockin of an N-terminal Cebpa mutation (Lp30 or L allele) 18 and a C-terminal Cebpa mutation (K313 duplication: K313KK or K allele). 11 This model for human AML enabled us to appropriately study the molecular and cellular background of leukemia initiation and maintenance.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Molecular and cellular effects of oncogene cooperation in a genetically accurate AML mouse model

et al. 2012

View full text Add to dashboard Cite

Biallelic CEBPA mutations and FMS-like tyrosine kinase receptor 3 (FLT3) length mutations are frequently identified in human acute myeloid leukemia (AML) with normal cytogenetics. However, the molecular and cellular mechanisms of oncogene cooperation remain unclear because of a lack of disease models. We have generated an AML mouse model using knockin mouse strains to study cooperation of an internal tandem duplication (ITD) mutation in the Flt3 gene with commonly observed CCAAT/enhancer binding protein alpha (C/EBPa) mutations. This study provides evidence that FLT3 ITD cooperates in leukemogenesis by enhancing the generation of leukemia-initiating granulocyte-monocyte progenitors (GMPs) otherwise prevented by a block in differentiation and skewed lineage priming induced by biallelic C/EBPa mutations. These cellular changes are accompanied by an upregulation of hematopoietic stem cell and STAT5 target genes. By gene expression analysis in premalignant populations, we further show a role of FLT3 ITD in activating genes involved in survival/transformation and chemoresistance. Both multipotent progenitors and GMP cells contain the potential to induce AML similar to corresponding cells in human AML samples showing that this model resembles human disease.

show abstract

Section: Resultssupporting

confidence: 91%

Section: Resultssupporting

confidence: 91%

Section: Mouse Strainsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Molecular and cellular effects of oncogene cooperation in a genetically accurate AML mouse model

et al. 2012

View full text Add to dashboard Cite

show abstract

Gene mutations differently impact the prognosis of the myelodysplastic and myeloproliferative classes of chronic myelomonocytic leukemia

et al. 2014

View full text Add to dashboard Cite

Initially classified in the myelodysplastic syndromes (MDSs), chronic myelomonocytic leukemia (CMML) is currently considered as a MDS/myeloproliferative neoplasm. Two classes-myelodysplastic and myeloproliferative-have been distinguished upon the level of the white blood cell count (threshold 13 G/L). We analyzed mutations in 19 genes reported in CMML to determine if and how these mutations impacted the respective prognosis of the two classes. We defined four major mutated pathways (DNA methylation, ASXL1, splicing, and signaling) and determined their prognostic impact. The number of mutated pathways impacted overall survival in the myelodysplastic class but not in the myeloproliferative class. The myeloproliferative class had a worse prognosis than the myelodysplastic class and was impacted by RUNX1 mutations only. Our results argue for a reclassification of CMML based on the myelodysplastic/myeloproliferative status.

show abstract

Phase 1 study of combinatorial sorafenib, G‐CSF, and plerixafor treatment in relapsed/refractory, FLT3‐ITD‐mutated acute myelogenous leukemia patients

et al. 2020

View full text Add to dashboard Cite

Stroma-leukemia interactions mediated by CXCR4, CD44, VLA4, and their respective ligands contribute to therapy resistance in FLT3-ITD-mutated acute myelogenous leukemia (AML). We conducted a phase 1 study with the combination of sorafenib (a FLT3-ITD inhibitor), plerixafor (a SDF-1/CXCR4 inhibitor), and G-CSF (that cleaves SDF-1, CD44, and VLA4). Twenty-eight patients with relapsed/refractory FLT3-ITDmutated AML were enrolled from December 2010 to December 2013 at three dose levels of sorafenib (400, 600, and 800 mg twice daily) and G-CSF and plerixafor were administered every other day for seven doses starting on day one. Sorafenib 800 mg twice daily was selected for the expansion phase. While no dose-limiting toxicities (DLT) were encountered in the four-week DLT window, hand-foot syndrome and rash were seen beyond the DLT window, which required dose reductions in most patients. The response rate was 36% (complete response (CR) = 4, complete remission with incomplete platelet recovery (CRp) = 4, complete remission with incomplete hematologic recovery (CRi) = 1, and partial response (PR) = 1) for the intention to treat population. Treatment resulted in 58.4 and 47 mean fold mobilization of blasts and CD34 / 38-stem/progenitor cells, respectively, to the circulation. Expression of the adhesion molecules CXCR4, CD44, and VLA4 on circulating leukemia cells correlated negatively with the mobilization of CD34+/38-, CD34+/38−/123+ "progenitor" cells (all P ≤ .002). Mass cytometry analysis of sequential samples from two patients demonstrated resistance emerging early on from sub-clones with persistent Akt and/or ERK signaling. In conclusion, the strategy of combined inhibition of FLT3 kinase and stromal adhesive interactions has promising activity in relapsed/refractory, FLT3-ITD-mutated AML, which warrants further evaluation in the front-line setting. 1 | INTRODUCTION The chemokine ligand SDF-1 and its receptor CXCR4 are highly relevant in FLT3-ITD-mutated acute myelogenous leukemia (AML). 1,2 Gautam Borthakur and Zhihong Zeng contributed equally to this study.

show abstract

FLT3 Mutations Confer Enhanced Proliferation and Survival Properties to Multipotent Progenitors in a Murine Model of Chronic Myelomonocytic Leukemia

Cited by 185 publications

References 52 publications

Molecular and cellular effects of oncogene cooperation in a genetically accurate AML mouse model

Molecular and cellular effects of oncogene cooperation in a genetically accurate AML mouse model

Gene mutations differently impact the prognosis of the myelodysplastic and myeloproliferative classes of chronic myelomonocytic leukemia

Phase 1 study of combinatorial sorafenib, G‐CSF, and plerixafor treatment in relapsed/refractory, FLT3‐ITD‐mutated acute myelogenous leukemia patients

Contact Info

Product

Resources

About