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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA076167-11
Application #
8703450
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Howcroft, Thomas K
Project Start
1999-04-01
Project End
2019-02-28
Budget Start
2014-04-18
Budget End
2015-02-28
Support Year
11
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Georgia Regents University
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Augusta
State
GA
Country
United States
Zip Code
30912
Hu, Tianxiang; Chong, Yating; Qin, Haiyan et al. (2018) The miR-17/92 cluster is involved in the molecular etiology of the SCLL syndrome driven by the BCR-FGFR1 chimeric kinase. Oncogene 37:1926-1938
Hu, Tianxiang; Wu, Qing; Chong, Yating et al. (2018) FGFR1 fusion kinase regulation of MYC expression drives development of stem cell leukemia/lymphoma syndrome. Leukemia :
Hu, Tianxiang; Chong, Yating; Lu, Sumin et al. (2018) miR-339 Promotes Development of Stem Cell Leukemia/Lymphoma Syndrome via Downregulation of the BCL2L11 and BAX Proapoptotic Genes. Cancer Res 78:3522-3531
Cowell, John K; Qin, Haiyan; Hu, Tianxiang et al. (2017) Mutation in the FGFR1 tyrosine kinase domain or inactivation of PTEN is associated with acquired resistance to FGFR inhibitors in FGFR1-driven leukemia/lymphomas. Int J Cancer 141:1822-1829
Wu, Qing; Bhole, Aaron; Qin, Haiyan et al. (2016) SCLLTargeting FGFR1 to suppress leukemogenesis in syndromic and de novo AML in murine models. Oncotarget 7:49733-49742
Cowell, John K; Qin, Haiyan; Chang, Chang-Sheng et al. (2016) A model of BCR-FGFR1 driven human AML in immunocompromised mice. Br J Haematol 175:542-545
Qin, H; Malek, S; Cowell, J K et al. (2016) Transformation of human CD34+ hematopoietic progenitor cells with DEK-NUP214 induces AML in an immunocompromised mouse model. Oncogene 35:5686-5691
Ren, Mingqiang; Qin, Haiyan; Wu, Qing et al. (2016) Development of ZMYM2-FGFR1 driven AML in human CD34+ cells in immunocompromised mice. Int J Cancer 139:836-40
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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