Stem Cell leukemia/lymphoma syndrome (SCLL) is the only malignancy consistently caused by activation of the FGFR1 kinase, in this case as a result of variant chromosome translocations leading to its constitutive and ligand independent activation. This syndrome is characterized by an atypical myeloproliferative disorder which frequently progresses to AML. In addition, SCLL patients develop T-cell or B-cell lymphomas. Survival of SCLL patients is <20% despite chemotherapy and bone marrow transplantation which is likely due to the 'stemness'of the disease. Clearly, novel approaches to the treatment of this disease are required to improve this dismal survival record. We have developed a transduction/transplantation approach in immunocompromized mice that expresses the various fusion kinases in normal human CD34+ cord blood cells ex vivo. Once transplanted the transduced stem cells home to the bone marrow and the disease develops exactly as in human patients. All mice develop an atypical myeloproliferative disorder (AMPD) and, depending on the specific rearrangement involved, may also develop T-cell or B-cell lymphoma. In all cases, the atypical MPD progresses to AML, and so this model provides an opportunity to establish the genetic events that accompany this progression, which has broad implications in the clinical management of MPD/AML, since ~25% of de novo AML (without an antecedent MPD/MDS) also overexpress FGFR1 and so a better understanding of its role in this disease could identify novel targets for treatment and provide the means to predict progression from the relatively benign disease to a far more aggressive AML which will kill the patient. These studies will define specific events that drive progression to AML in human cells.
In Specific Aim 1, therefore, we will use RNASeq and Exome sequencing to define the genetic events that accompany the progression of AMPD to AML and verify these changes using cell reagents we have developed. Candidate targets will be used in in vivo therapeutic strategies in the human CD34+ mouse model. Of all of the variant chimeric kinases associated with SCLL, the BCR-FGFR1 fusion gene produces a far more aggressive disease, which is possibly due to a contribution of the BCR kinase domain. Leukemia/lymphomas driven by this fusion gene respond poorly to targeted therapies.
In Specific Aim 2, therefore, we will use mutant forms of BCR- FGFR1 and RNASeq approaches to define the genetic events that generate this more aggressive disease. Constitutive, ligand independent activation of FGFR1 kinases implies the inappropriate activation of downstream targets through tyrosine phosphorylation.
In Specific Aim 3 and we will use a phosphoproteomics approach to identify specific targets of the chimeric FGFR1 kinases and evaluate whether preventing their activation will suppress leukemogenesis.
One of the major unresolved issues in leukemia research is how myeloproliferative disorders progress to AML. An understanding of this process would provide a means of predicting which patients are likely to progress so treatment could be started early and determining the genetic changes that accompany this transition could identify targets that can be used to treat this subtype of AML. The FGFR1 mouse models described in this proposal offer the opportunity to address this issue in a homogeneous system.
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|Qin, Haiyan; Wu, Qing; Cowell, John K et al. (2016) FGFR1OP2-FGFR1 induced myeloid leukemia and T-cell lymphoma in a mouse model. Haematologica 101:e91-4|
|Ren, Mingqiang; Qin, Haiyan; Kitamura, Eiko et al. (2013) Dysregulated signaling pathways in the development of CNTRL-FGFR1-induced myeloid and lymphoid malignancies associated with FGFR1 in human and mouse models. Blood 122:1007-16|
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|Ren, Mingqiang; Tidwell, Josephine A; Sharma, Suash et al. (2012) Acute progression of BCR-FGFR1 induced murine B-lympho/myeloproliferative disorder suggests involvement of lineages at the pro-B cell stage. PLoS One 7:e38265|
|Ren, MingQiang; Cowell, John K (2011) Constitutive Notch pathway activation in murine ZMYM2-FGFR1-induced T-cell lymphomas associated with atypical myeloproliferative disease. Blood 117:6837-47|
|Ren, Mingqiang; Qin, Haiyan; Ren, Ruizhe et al. (2011) Src activation plays an important key role in lymphomagenesis induced by FGFR1 fusion kinases. Cancer Res 71:7312-22|
|Ren, Mingqiang; Li, Xiurong; Cowell, John K (2009) Genetic fingerprinting of the development and progression of T-cell lymphoma in a murine model of atypical myeloproliferative disorder initiated by the ZNF198-fibroblast growth factor receptor-1 chimeric tyrosine kinase. Blood 114:1576-84|
|Kasyapa, Chitta; Gu, Ting-Lei; Nagarajan, Lalitha et al. (2009) Phosphorylation of the SSBP2 and ABL proteins by the ZNF198-FGFR1 fusion kinase seen in atypical myeloproliferative disorders as revealed by phosphopeptide-specific MS. Proteomics 9:3979-88|
|Kasyapa, Chitta S; Kunapuli, Padmaja; Cowell, John K (2007) HSPA1A is an important regulator of the stability and function of ZNF198 and its oncogenic derivative, ZNF198-FGFR1. J Cell Biochem 102:1308-17|
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