Mislocalized Activation of Oncogenic RTKs Switches Downstream Signaling Outcomes

Choudhary, Chunaram; Olsen, Jesper V.; Brandts, Christian; Cox, Jürgen; Reddy, Pavankumar N.G.; Böhmer, Frank D.; Gerke, Volker; Schmidt-Arras, Dirk; Berdel, Wolfgang E.; Müller‐Tidow, Carsten; Mann, Matthias; Serve, Hubert

doi:10.1016/j.molcel.2009.09.019

Cited by 283 publications

(311 citation statements)

References 59 publications

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“…We also observed a higher frequency of LT-HSC in KLI chimeras (Supplementary Figure 4F). However, there is evidence that Flt3 ITD/ þ mice have lower surface expression of the FLT3 receptor (Jacobsen, personal communication) probably due to entrapment of the FLT3 ITD in the endoplasmic reticulum 25,26 and therefore identification of LT-and ST-HSC using FLT3 may be problematic. Consequently, we decided to rely on expression of CD150 and CD48 (Figures 3a and b) to identify LT-HSC (LSKCD150 þ CD48 À ) and MPP (CD150 À CD48 þ ).…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2012

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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.

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Section: Resultsmentioning

confidence: 99%

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

et al. 2012

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“…Recently, it has been reported that the oncogenic mutant of fms-like tyrosine kinase-internal tandem duplication aberrantly activates STAT5 when localized at ER, but fails to activate MAPK and AKT signaling. 17 Thus, this raises the possibility that involvement of the STAT3 pathway in ALK del2-3 -expressing cells resembles the fms-like tyrosine kinase-internal tandem duplication mutant. 17 Immunofluorescence staining and the endoglycosidase H sensitivity assay revealed that ALK del2-3 is mainly located at ER and aberrantly activates the STAT3 pathway from ER.…”

Section: Discussionmentioning

confidence: 98%

“…17 Thus, this raises the possibility that involvement of the STAT3 pathway in ALK del2-3 -expressing cells resembles the fms-like tyrosine kinase-internal tandem duplication mutant. 17 Immunofluorescence staining and the endoglycosidase H sensitivity assay revealed that ALK del2-3 is mainly located at ER and aberrantly activates the STAT3 pathway from ER. Taken together, our results suggest that intracellular activation of ALK del2-3 switches downstream signaling to the ALK pathway.…”

Section: Discussionmentioning

confidence: 98%

“…It has been previously reported that intracellular fms-like tyrosine kinase-internal tandem duplication activation induces an aberrant downstream signaling outcome. 17 To determine whether ALK del2-3 expresses at the cell surface and mediates signals from endoplasmic reticulum (ER), we analyzed localization and deglycosidation of ALK del2-3 in NB-1 cells and wild-type ALK in NH-12 cells. Immunofluorescence staining revealed that ALK in NB-1 cells was almost colocalized with PDI, whereas ALK in NH-12 cells was largely located at the plasma membrane ( Figure 5a).…”

Section: Detection Of a Short-form Alk Protein In Nb-1 Cellsmentioning

confidence: 99%

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Aberrant activation of ALK kinase by a novel truncated form ALK protein in neuroblastoma

et al. 2012

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Anaplastic lymphoma kinase (ALK) was originally identified from a rare subtype of non-Hodgkin's lymphomas carrying t(2;5)(p23;q35) translocation, where ALK was constitutively activated as a result of a fusion with nucleophosmin (NPM). Aberrant ALK fusion proteins were also generated in inflammatory fibrosarcoma and a subset of non-small-cell lung cancers, and these proteins are implicated in their pathogenesis. Recently, ALK has been demonstrated to be constitutively activated by gene mutations and/or amplifications in sporadic as well as familial cases of neuroblastoma. Here we describe another mechanism of aberrant ALK activation observed in a neuroblastoma-derived cell line (NB-1), in which a short-form ALK protein (ALK del2-3 ) having a truncated extracellular domain is overexpressed because of amplification of an abnormal ALK gene that lacks exons 2 and 3. ALK del2-3 was autophosphorylated in NB-1 cells as well as in ALK del2-3 -transduced cells and exhibited enhanced in vitro kinase activity compared with the wild-type kinase. ALK del2-3 -transduced NIH3T3 cells exhibited increased colony-forming capacity in soft agar and tumorigenicity in nude mice. RNAi-mediated ALK knockdown resulted in the growth suppression of ALK del2-3 -expressing cells, arguing for the oncogenic role of this mutant. Our findings provide a novel insight into the mechanism of deregulation of the ALK kinase and its roles in neuroblastoma pathogenesis.

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“…We therefore looked downstream from FLT3 to investigate whether signaling differences occurred during coculture on stroma. Of particular interest was STAT5, whose phosphorylation and subsequent activation is a hallmark of the oncogenic FLT3-ITD pathway (29,30). In MV4-11 cells, SU5614 inhibited phosphorylation of STAT5 in suspension and when cocultured with EL08-1D2 ( Fig.…”

Section: Flt3-itd-specific Downstream Signaling Is Uncoupled From Fltmentioning

confidence: 99%

Stromal Niche Cells Protect Early Leukemic FLT3-ITD+ Progenitor Cells against First-Generation FLT3 Tyrosine Kinase Inhibitors

et al. 2011

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Targeting constitutively activated FMS-like tyrosine kinase 3 [(FLT3); FLT3-ITD] with tyrosine kinase inhibitor (TKI) in acute myeloid leukemia (AML) leads to clearance of blasts in the periphery but not in the bone marrow, suggesting a protective effect of the marrow niche on leukemic stem cells. In this study, we examined the effect of stromal niche cells on CD34 þ progenitors from patients with FLT3-ITD þ or wild-type FLT3 (FLT3-WT) AML treated with the TKIs SU5614 or sorafenib. TKIs effectively and specifically inhibited FLT3 and increased the fraction of undivided progenitors in both FLT3-ITD þ and FLT3-WT samples. Treatment with SU5614 and sorafenib also reduced the number of mature leukemic progenitors, whereas contact with stroma protected against this cell loss. In contrast, primitive long-term progenitors from both FLT3-ITD þ and FLT3-WT AML were resistant to TKIs. Additional contact with niche cells significantly expanded long-term FLT3-ITD þ but not FLT3-WT progenitors in the presence of SU5614 but not that of sorafenib. Thus, TKIs with first-generation inhibitors fail to eradicate early leukemic stem/progenitor cells in FLT3-ITD þ AML. Further, we defined a specific interaction between FLT3-ITD þ progenitors and niche cells that enables the maintenance of leukemic progenitors in the presence of TKI. Collectively, our findings suggest that molecular therapy may have unpredicted effects on leukemic progenitors, underscoring the necessity of developing strategies to selectively eliminate the malignant stem cell clone. Cancer Res; 71(13); 4696-706. Ó2011 AACR.

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Mislocalized Activation of Oncogenic RTKs Switches Downstream Signaling Outcomes

Cited by 283 publications

References 59 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

Aberrant activation of ALK kinase by a novel truncated form ALK protein in neuroblastoma

Stromal Niche Cells Protect Early Leukemic FLT3-ITD+ Progenitor Cells against First-Generation FLT3 Tyrosine Kinase Inhibitors

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