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Constitutive Activation of FLT3 Stimulates Multiple Intracellular Signal Transducers and Results in Transformation K-F Tse1, G Mukherjee2 and D Small1,3

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Constitutive Activation of FLT3 Stimulates Multiple Intracellular Signal Transducers and Results in Transformation K-F Tse1, G Mukherjee2 and D Small1,3 Leukemia (2000) 14, 1766–1776 2000 Macmillan Publishers Ltd All rights reserved 0887-6924/00 $15.00 www.nature.com/leu Constitutive activation of FLT3 stimulates multiple intracellular signal transducers and results in transformation K-F Tse1, G Mukherjee2 and D Small1,3 Departments of 1Oncology, 3Pediatrics and 2Comparative Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA Aberrant expression of FLT3 has been found in most cases of subunit of phosphatidylinositol 3Ј-kinase (PI3K), RAS/GTPase B-lineage ALL and AML, and subsets of T cell ALL, CML in blast activating protein, phospholipase C-␥, VAV, SHC, GRB2 and crisis and CLL. In 20% of patients with AML the receptor has 21–27 small internal tandem duplications of the juxtamembrane CBL. region which appear to contitutively activate the receptor. To c-FMS and c-KIT are over-expressed by many cases of investigate whether FLT3 activation could play a role in leuke- myeloid leukemia but not often in ALL. In contrast, data from mia, we generated a constitutively activated FLT3 by fusing its our previous studies and others have demonstrated aberrant cytoplasmic domain to the helix–loop–helix domain of TEL in expression of FLT3 in most cases of B-lineage ALL and AML analogy to the fusion that occurs with TEL-PDGFR in CMML. as well as subsets of T-ALL and CML samples.28–31 Over- In vitro translation assays demonstrated oligomerization and intrinsic tyrosine kinase activity of the TEL-FLT3 chimeric expression occurs at both RNA and protein levels and leads receptor. Constitutively activated TEL-FLT3 conferred IL-3 to a functional receptor as addition of FL in vitro causes phos- independence and long-term proliferation to transfected Ba/F3 phorylation of the receptor and a proliferative response in cells. Immunoblot analyses showed that JAK 2, STAT 3, STAT some cases of leukemic cells.28,32,33 5a, STAT 5b and CBL were tyrosine-phosphorylated in TEL- Expression of mRNA for the FLT3 ligand (FL) has also been FLT3 expressing Ba/F3 cells in the absence of IL-3. These data detected in virtually all leukemic-derived cell lines, bone mar- suggest a possible role for the JAK/STAT pathway in FLT3 sig- 9,34–36 naling. Transplantation of TEL-FLT3 expressing Ba/F3 cells into row stroma and endothelial cells. Coexpression of syngeneic mice caused mortality in all mice by 3 weeks after SCF/c-KIT and CSF-1/c-FMS pairs has also been reported in injection. Histopathologic analysis demonstrated a massive cases of leukemia.37–39 Coexpression of both FLT3 and its infiltration of mononuclear cells in the liver, spleen and bone ligand by the same leukemia cell suggest a possible marrow. The mimicking of naturally occurring TEL fusions pro- autocrine/paracrine/intracrine signaling loop which could vides an approach to assess aspects of the biology of activated contribute to the development or maintenance of FLT3, or other receptor-type tyrosine kinases (RTKs) in leu- 40,41 kemic transformation. Leukemia (2000) 14, 1766–1776. leukemia. Keywords: FLT3; STAT5; JAK2; CBL; transformation; leukemia In addition, small internal tandem duplications in the juxta- membrane portion of the receptor have been discovered in approximately 20% of patients with AML.42–45 The mutation Introduction appears to activate the kinase domain of the receptor through constitutive dimerization.46 While the consequence of FLT3 Signal transduction initiated by the interactions of hemato- activation is unproven, it is conceivable that constitutively poietic growth factors/cytokines with specific receptors is criti- activated FLT3 plays a role in the proliferation and block in cal for regulating normal hematopoietic cell growth and differ- differentiation that characterizes leukemia. entiation.1–3 Several of the hematopoietic growth factors In this report, we model an activated FLT3 receptor to study utilize members of the type III RTK family. This family is its possible role in leukemia. Our approach was to generate characterized by five immunoglobulin-like folds in the extra- a constitutively activated FLT3 receptor by fusion of the entire cellular domain, a single transmembrane domain and an inter- cytoplasmic domain of FLT3 to the helix–loop–helix (HLH; rupted tyrosine kinase domain in the intracellular region.4,5 also called ‘pointed’) domain of TEL. TEL is a member of the Members of this receptor family include two receptors which ETS family of transcription factors, and contains a highly con- served amino-terminal HLH domain which functions to play important roles in hematopoiesis, c-KIT and c-FMS, two 47,48 receptors for PDGF, and FLT3, the most recently discovered mediate protein–protein interaction. TEL is notable for its member of this family.6 involvement in several chromosomal translocations which During normal hematopoiesis, FLT3 is primarily expressed result in the generation of chimeric proteins such as TEL- + PDGF␤R in CMML, TEL-ABL in AML and TEL-JAK2 in within the CD34 hematopoietic stem/progenitor cell fraction 49,50 as well as a specific population of CD34− cells.7–10 FLT3 ALL. All of these fusions resulted in activated tyrosine kin- ase domains and cause transformation when expressed in appears to play a role in the maintenance of pluripotent hema- 51–54 topoietic stem cells7,11,12 and development of B cell progen- hematopoietic cells. itors,13–15 and dendritic cells.11,16–18 Similar to other class III RTKs, FLT3 is activated by ligand (FLT3 ligand, FL)-dependent dimerization and Materials and methods transphosphorylation of tyrosine residues.19,20 Subsequent signal transduction is mediated through association and/or Construction of chimeric receptors phosphorylation of cytoplasmic substrates including the p85 The construction of the TEL-FLT3 fusions was performed by polymerase chain reaction (PCR) as illustrated in Figure 1a. To generate DNA for the HLH domain of TEL, total RNA from Correspondence: D Small, The John Hopkins Oncology Center, Bunt- ing-Blaustein Cancer Research Building, Room 253, 1650 Orleans K562 cells was reverse transcribed and the resulting cDNA Street, Baltimore, Maryland 21231-1000, USA; Fax: 410-955-8897 was used as a template for 35 cycles of PCR: 94°C, 50°C and Received 30 March 2000; accepted 30 June 2000 72°C (1 min each) using Taq polymerase (GIBCO, Gaithers- Activated FLT3 results in leukemic transformation K-F Tse et al 1767 Figure 1 (a) Schematic illustration of the construction of TEL-FLT3 and kinase deletion mutant FLT3 (del) and TEL-FLT3 (del) constructs. (b) Oligomerization of TEL-FLT3 in vitro. TEL-FLT3 and TEL-FLT3 (del) cDNA constructs were expressed either alone or together by in vitro transcrip- tion and translation using radiolabeled 35S methionine. Labeled lysates were immunoprecipitated with anti-FLT3 antibody specific for the car- boxyl-terminal of FLT3 (lanes 4–6) or with rabbit IgG as a control (lanes 7–9). Total reaction mixtures (lanes 1–3) and immunoprecipitates (lanes 4–9) were resolved by SDS-PAGE, transferred to a membrane, and exposed to film. T/F: TEL-FLT3; T/F (d): TEL-FLT3 (del). burg, MD, USA) with a primer (P1) containing a Sal1 site and (P4) containing FLT3 3Ј sequences: 5Ј-AGCTGTTGCGTTCAT- TEL 5Ј sequences: 5Ј-TGATCTCTCTCGCTGTGA-3Ј and a CAC-3Ј. The resulting TEL and FLT3 PCR products were primer (P2) containing sequences for both TEL and FLT3: 5Ј- mixed, boiled, allowed to reanneal and used as templates in CTTTTTGTACTTGTGACA (TEL)-TTCTTCATGGTTCTGATG a second round of PCR using the P1 and the P4 primers for (FLT3)-3Ј.7,49 To generate the cytoplasmic domain of FLT3, 30 cycles of amplification: 94°C (1 minute), 50°C (1 min) and FLT3 plasmid DNA was amplified by PCR for 30 cycles: 94°C, 72°C (2 min). The TEL-FLT3 fusion product was digested with 55°C and 72°C (1 min each) with a 5Ј primer (P3) containing Sal1 and BstEII and ligated to the Sal1 and BstEII digested full- both TEL and FLT3 sequences: 5Ј-CATCAGAACCATGAAGAA length FLT3 cDNA. The chimeric Tel-FLT3 product was then (TEL)-TGTCACAAGTACAAAAAG (FLT3)-3Ј and a 3Ј primer subcloned into the pCIneo expression vector (Promega, Madi- Leukemia Activated FLT3 results in leukemic transformation K-F Tse et al 1768 son, WI, USA). Partial kinase domain deletion mutants for Cell culture and transfection both native FLT3 (FLT3 (del)) and chimeric TEL-FLT3 (Tel- FLT3 (del)) were created by digesting each plasmid with The murine IL-3-dependent pro-B cell line, Ba/F3, was main- EcoR1 to remove the region coding for the C-terminal 233 tained in RPMI 1640 medium (GIBCO) supplemented with amino acids of the kinase domain. The sequences of the 10% fetal calf serum (FCS; Gemini Bio-Products, Calabasas, recombinant constructs were confirmed by the dideoxy CA, USA) and 1 ng/ml IL-3. Ba/F3 cells were transfected with sequencing method. vector, TEL (nucleotides 25–486),49 FLT3, FLT3 (del), TEL- FLT3 and TEL-FLT3 (del) plasmid DNA by electroporation at 300 mV/960 ␮F (Bio-Rad, Richmond, CA, USA). Transfected Cytokines and antibodies cells were cultured in IL-3 containing medium for 48 h and then selected in 1 mg/ml G418 (GIBCO) for a period of 2 Recombinant murine IL-3 (IL-3) and recombinant human FLT3 weeks. The ability of the cells to survive in the absence of IL- ligand were purchased from R & D Systems (Minneapolis, 3 was determined by trypan blue exclusion after plating MN, USA). Rabbit polyclonal antibodies against JAK 1, JAK 2, aliquots of the washed cells in 96-well plates. Transfected cell JAK 3, STAT 1, STAT 3, STAT 5a, STAT 5b, and CBL were lines were then subcloned by limiting dilution. For obtained from Santa Cruz Biotechnology (Santa Cruz, determination of growth properties of stably transfected Ba/F3 CA,USA).
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