Combination of c-SRC and FLT3 Inhibitors Has An Additive Inhibitory Effect on FLT3 ITD but Not on FLT3 TKD Positive Cells

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2892-2892 ◽  
Author(s):  
Hannes Leischner ◽  
Rebekka Grundler ◽  
Corinna Albers ◽  
Anna Lena Illert ◽  
Katharina Götze ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Growth Inhibition ◽  
Conflicts Of Interest ◽  
Point Mutations ◽  
Inhibitory Effect ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Myeloproliferative Disease ◽  
Activating Mutations ◽  
Flt3 Inhibitors

Abstract Abstract 2892 Activating mutations of FLT3 are frequent in patients with AML. Two types of mutations are most common: Internal tandem duplications (ITD) of the juxtamembrane domain in approximately 30% of patients and point mutations within the second tyrosine kinase domain (TKD) in about 7% of AML patients. Patients carrying the FLT3-ITD mutation have a significantly worse prognosis whereas FLT3-TKD mutations do not appear to influence the clinical outcome. Studies have shown that mice receiving a transplant of bone marrow expressing FLT3 ITD develop a myeloproliferative disease. In contrast, mice which were transplanted with FLT3 TKD infected bone marrow, suffer from a lymphoid disease. Thus, both FLT3 mutations seem to exert different biological functions. Interestingly, FLT3-ITD but not FLT3-TKD or FLT3-WT leads to a strong activation of the STAT5 signaling pathway. Recently we have shown that c-SRC is the crucial signaling mediator of FLT3 ITD to activate STAT5. Based on these findings we investigated the effect of FLT3 inhibitors (Midostaurin, Sorafenib and Sunitinib) in combination with c-SRC inhibitors (Dasatinib and PD166-326) on FLT3 ITD and FLT3 TKD murine and human cell lines as well as on primary patient material. In FLT3 ITD expressing murine myeloid 32D cells c-SRC inhibitors in combination with FLT3 inhibitors showed clear additive effects on growth inhibition, apoptosis and activation of STAT5. In contrast, c-SRC inhibitors had no additional effects in FLT3 TKD expressing cells. Accordingly, a strong additive effect of c-SRC and FLT3 inhibitors could also be demonstrated in the FLT3 ITD positive human AML cell line MV4-11. Finally FLT3 ITD and FLT3 TKD positive primary human AML cells were investigated. We were able to detect a significant additional growth inhibition of FLT3 ITD positive human cells by combining c-SRC and FLT3 inhibitors. In contrast, no further growth inhibition was observed by c-SRC inhibition in primary AML cells expressing the FLT3 TKD mutation. Together our results confirm c-SRC as a crucial signaling mediator in FLT3-ITD but not FLT3-TKD positive AML. The combination of FLT3 and c-SRC inhibitors warrants further investigation in FLT3 ITD positive AML. Disclosures: No relevant conflicts of interest to declare.

SRC Is a Critical Signaling Mediator in FLT3-ITD Positive AML.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 477-477
Author(s):  
Hannes Leischner ◽  
Rebekka Grundler ◽  
Corinna Albers ◽  
Anna Lena Illert ◽  
Karsten Spiekermann ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Conflicts Of Interest ◽  
Point Mutations ◽  
Kinase Domain ◽  
Sh2 Domain ◽  
Control Group ◽  
Tyrosine Kinase Domain ◽  
Myeloproliferative Disease ◽  
Activating Mutations ◽  
Tandem Duplications

Abstract Abstract 477 Activating mutations of FLT3 are frequent in patients with AML. Two types of mutations are most common: Internal tandem duplications (ITD) of the juxtamembrane domain in approximately 30% of patients and point mutations within the second tyrosine kinase domain (TKD) in about 7% of AML patients. Patients carrying the FLT3-ITD mutation have a significantly worse prognosis whereas FLT3-TKD mutations do not appear to influence the clinical outcome. Studies have shown that mice receiving a transplant of bone marrow expressing FLT3 ITD develop a myeloproliferative disease. In contrast, mice which were transplanted with FLT3 TKD infected bone marrow, suffer from a lymphoid disease. Thus, both FLT3 mutations seem to exert different biological functions. Interestingly, FLT3-ITD but not FLT3-TKD or FLT3-WT leads to a strong activation of the STAT5 signaling pathway. Therefore, STAT5 activation may be responsible for the observed differences in biology. Here we investigated the signalling pathways leading to STAT5 activation downstream of FLT3-ITD. FLT3-ITD does not bind STAT5 directly nor does it activate the classical JAK2 pathway. Instead FLT3-ITD utilizes c-Src to activate STAT5. Co-immunoprecipitations and GST pull downs revealed a strong and exclusive interaction between Src and FLT3 ITD, which is mediated by the Src-SH2 domain. This interaction is absent in FLT3-TKD or FLT3-WT after ligand stimulation. The sequence duplication in FLT3-ITD leads to additional potential Src-SH2 binding sites. We identified tyrosines 589 and 591 of FLT3-ITD to be essential for Src binding and subsequent STAT5 activation. Specific Src inhibitors or Src-siRNA blocked STAT5 activation and growth induced by FLT3-ITD but not FLT3-TKD. FLT3-ITD positive cells with a stable Src knockdown injected into syngenic mice led to a leukemic disease with a significant delayed onset and prolonged survival in comparison to the control group. Finally, a combination of FLT3 and Src inhibitors was tested. This combination was highly efficient in FLT3-ITD positive cells but not in FLT-TKD positive cells. Together these findings show that Src plays an important role in the signalling of FLT3-ITD but not FLT3-TKD. Thus, Src might be an interesting therapeutic target for FLT3-ITD positive AML. Disclosures: No relevant conflicts of interest to declare.

FLT3 ITD and FLT3 Tyrosine Kinase Domain Mutants Induce Different Phenotypes in a Murine Bone Marrow Transplant Model.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3371-3371
Author(s):  
Rebekka Grundler ◽  
Cornelius Miething ◽  
Christian Thiede ◽  
Christian Peschel ◽  
Justus Duyster
Keyword(s):  
Bone Marrow ◽  
Clinical Outcome ◽  
Tyrosine Kinase ◽  
Lymph Nodes ◽  
Point Mutations ◽  
Marrow Transplant ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Myeloproliferative Disease ◽  
Transplant Model

Abstract Activating mutations of FLT3 are frequent in patients with acute myeloid leukemia (AML). Two distinct types of FLT3 mutations are most common: Internal tandem duplication (ITD) of the juxtamembrane domain-coding sequence in approximately 30% of patients with AML and point mutations within the second tyrosine kinase domain (TKD) in about 7% of AML patients. Patients carrying the FLT3 ITD mutation seem to have a significantly worse prognosis, whereas the impact of TKD mutations on clinical outcome has not yet been determined. Recently, point mutations within the activation loop of FLT3 were also found in a significant percentage of infant and childhood acute lymhoblastic leukemia (ALL). Previous studies demonstrate that mice receiving transplants of bone marrow retrovirally infected with FLT3 ITD develop a myeloproliferative disease. The effect of FLT3 TKD mutations in vivo has not yet been investigated. To examine the transforming properties of FLT3 TKD mutants in primary hematopoietic cells, we used a bone marrow transplant model (BMT). Therefore we transduced bone marrow with retrovirus expressing either FLT3 D835Y or FLT3 I836M+R and transplanted it to lethally irradiated syngeneic recipient mice. As control we also transplanted mice with FLT3 WT and ITD infected bone marrow, respectively. We found that mice transplanted with FLT3 ITD developed a myeloproliferative disorder in mice, as previously described. In contrast, mice transplanted with FLT3 TKD mutants developed a lymphoid disease with distinct hematologic manifestation. Most recipients of FLT3 TKD transduced bone marrow developed T lymphoma syndrome, characterized by massive enlargement of thymus and lymph nodes. Some mice developed a B lymphoid leukemia with splenomegaly and enlarged lymph nodes. Interestingly, the disease latency of 53 to 183 days (median 102 days) of FLT3 TKD mutants contrasted with FLT3 ITD mice, which succumbed myeloproliferative disease within 53 to 70 days (median 58 days). The lymphoid manifestation and longer latency of FLT3 TKD in a murine BMT model together with the absent influence of FLT3 TKD mutations on clinical outcome of AML patients suggest differences in cell signaling between FLT3 TKD mutants and FLT3 ITD. The TKD mutants seem to require lymphoid cell context for full malignant transformation, whereas FLT3 ITDs transform myeloid cells.

Involvement of a B1 Progenitor In a Murine Model of BCR-FGFR1 Induced Leukemogenesis.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1221-1221
Author(s):  
Josephine A Tidwell ◽  
Mingqiang Ren ◽  
John K Cowell
Keyword(s):  
Bone Marrow ◽  
B Cell ◽  
Murine Model ◽  
Conflicts Of Interest ◽  
Flow Analysis ◽  
Kinase Domain ◽  
Myeloproliferative Disease ◽  
Leukemic Transformation ◽  
A Cell

Abstract Abstract 1221 Constitutive activation of the FGFR1 kinase domain through rearrangement with dimerization domains from various proteins leads to an atypical myeloproliferative disease (MPD). Although the majority of these rearrangements result in development of T-cell leukemia/lymphoma, in the case of the BCR-FGFR1 rearrangement the phenotype is predominantly a myeloid and B cell MPD. To investigate the etiology of this disease, a murine model of BCR-FGFR1 was created using a bone marrow transduction/transplantation approach. Consistent with the human disease, recipient mice developed clear myeloproliferations marked by CML-like basophilia as well as extramedullary leukemic transformation containing myelo- or lymphoblasts, with neoplasms of myeloid and B cell lineages. Flow analysis demonstrated a CD43+ phenotype in leukemic B cells suggesting a block in the differentiation of pro-B progenitor cells. A cell line (BBC1) has now been established with this immature B cell immunophenotype albeit B220-, consistent with a recently described B1 progenitor. These cells can differentiate in vitro with characteristics of both macrophage and dendritic lineages. When BBC1 cells are injected into normal mice, leukemogenesis marked by a hypercellular bone marrow and splenomegaly is induced. Although BBC cells show the same progenitor B cell immunophenotype seen in the parent cells throughout the hematopoietic system, tumor cells in the peritoneum lose CD43 expression, down-regulate CD19 expression and upregulate CD11b and F4/80 demonstrating a capacity to differentiate in this environment. In this model, therefore, the etiology of BCR-FGFR1 disease closely mimics that seen in humans and we have identified a likely B cell subtype involved in leukemic transformation. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Dual Mechanism Inhibitor Control and Pharmacological Utility of Drug Resistance FLT3-ITD in Acute Myeloid Leukemia Cells

2021 ◽  
Vol 1 (1) ◽  
Author(s):  
Maria Rogdaki ◽  
Xinhua Xiao
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Point Mutations ◽  
Kinase Domain ◽  
Genetic Alterations ◽  
Tyrosine Kinase Domain ◽  
Tubulin Inhibitor ◽  
Flt3 Mutations ◽  
Flt3 Inhibitors ◽  
Acute Myeloid

FLT3 mutations are among the most common genetic alterations in acute-myeloid leukemia (AML). They are associated with poor prognosis. Multiple FLT3 inhibitors have been in clinical evaluation at various stages. Resistance to FLT3 inhibitors due to acquired point mutations in the tyrosine-kinase domain (TKD), have limited the effectiveness of treatments. A “gatekeeper” mutation (F691L), is also resistant to most FLT3 inhibitors. New therapies are therefore needed. FLT3 inhibitors are needed to protect against FLT3-TKD mutations and FLT3 internal tandem duplicate (FLT3–ITD). We identified KX2-391, a dual FLT3/tubulin inhibitor, and examined its efficacy and mechanisms for overcoming drug-resistant FLT3ITD-TKD mutations. KX2-391 had potent growth inhibitory effects and apoptosis promoting effects on AML cell lines that harbor FLT3-ITD mutations. KX2-391 orally administered significantly prolonged the survival time of a murine model with leukemia caused by FLT3ITD-F691L. KX2-391 also inhibited growth of primary AML cells that express FLT3ITD-F691L and 2 primary cells that are FLT3ITD-D835Y. Preclinical data suggest that KX2-391 is a promising FLT3 inhibitor. The treatment of AML patients with FLT3 mutations, particularly refractory/relapsed patients suffering from F691L or other FLT3TKD mutations.

Activating FLT3 Mutations in CD4+/CD8− Pediatric T-Cell Acute Lymphoblastic Leukemias.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1465-1465
Author(s):  
Pieter Van Vlierberghe ◽  
Jules P.P. Meijerink ◽  
Ronald W. Stam ◽  
Wendy van der Smissen ◽  
Elisabeth R. van Wering ◽  
...  
Keyword(s):  
T Cell ◽  
Tyrosine Kinase ◽  
Point Mutations ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Activating Mutations ◽  
Activated State ◽  
Flt3 Mutations ◽  
Genetic Aberration ◽  
High Level

Abstract Activating mutations in the FMS-like tyrosine kinase 3 gene (FLT3) are the most common genetic aberration in acute myeloid leukemia (AML). Internal tandem duplications (ITD) in the juxtamembrane (JM) domain, or point mutations (PM) in the activation loop of the tyrosine kinase domain lead to a constitutive activated state of the FLT3 tyrosine kinase. Recently, FLT3 mutations were identified in a cohort of 69 adult T-ALL patients, showing that this genetic abnormality is not only restricted to myeloid leukemias. To validate the incidence of FLT3 mutations in pediatric T-ALL and investigate its relation to outcome and other clinical and immunophenotypical parameters, we screened 72 diagnostic pediatric T-ALL samples. FLT3/ITD mutations were identified in 2/72 pediatric T-ALLs (2.7%), whereas 0/72 showed point mutations in the kinase domain. Immunophenotypic analysis revealed a similar profile for both FLT3 mutated patient samples, i.e. TdT+, CD2+, CD5+, CD7+, CD4+/CD8−, cytoplasmic CD3+, surface CD3− and CD10−. Although representing early T-cell differentiation stages for both patient samples, these cases seem to have a more advanced immunophenotype compared to the FLT3 mutated adult T-ALL cases, previously described (CD34+, CD4−/CD8−). Both FLT3 mutated patients showed high level LYL1 and LMO2 expression. In addition, both pediatric samples contained a HOX11L2 translocation, which was not present in the FLT3 mutated adult T-ALL cases. The first FLT3 mutated patient suffered a relapse 13 months after initial diagnosis, whereas the other is still in continued complete remission for 61+ months. Interestingly, the relapse material showed no FLT3/ITD mutation, indicating that the FLT3 mutated T-ALL subclone seems to be effectively eradicated by current chemotherapy. These data suggest that the application of FLT3 inhibitors for FLT3-mutated T-ALLs, as recently suggested in literature, may not further improve treatment outcome in pediatric T-ALL.

AML-associated Flt3 kinase domain mutations show signal transduction differences compared with Flt3 ITD mutations

Blood ◽  
2005 ◽  
Vol 106 (1) ◽  
pp. 265-273 ◽  
Author(s):  
Chunaram Choudhary ◽  
Joachim Schwäble ◽  
Christian Brandts ◽  
Lara Tickenbrock ◽  
Bülent Sargin ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Target Genes ◽  
Kinase Inhibitor ◽  
Point Mutations ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Activating Mutations ◽  
Myeloid Progenitor ◽  
Myeloid Progenitor Cells ◽  
Kinase Domain Mutations

Activating mutations of Flt3 are found in approximately one third of patients with acute myeloid leukemia (AML) and are an attractive drug target. Two classes of Flt3 mutations occur: internal tandem duplications (ITDs) in the juxtamembrane and point mutations in the tyrosine kinase domain (TKD). We and others have shown that Flt3-ITD induced aberrant signaling including strong activation of signal transducer and activator of transcription 5 (STAT5) and repression of CCAAT/estradiol-binding protein α (c/EBPα) and Pu.1. Here, we compared the signaling properties of Flt3-ITD versus Flt3-TKD in myeloid progenitor cells. We demonstrate that Flt3-TKD mutations induced autonomous growth of 32D cells in suspension cultures. However, in contrast to Flt3-ITD and similar to wild-type Flt3 (Flt3-WT), Flt3-TKD cannot support colony formation in semisolid media. Also, in contrast to Flt3-ITD, neither Flt3-WT nor Flt3-TKD induced activation or induction of STAT5 target genes. Flt3-TKD also failed to repress c/EBPα and Pu.1. No significant differences were observed in receptor autophosphorylation and the phosphorylation of Erk-1 and -2, Akt, and Shc. Importantly, TKD but not ITD mutations were a log power more sensitive toward the tyrosine kinase inhibitor protein kinase C 412 (PKC412) than Flt3-WT. In conclusion, Flt3-ITD and Flt3-TKD mutations display differences in their signaling properties that could have important implications for their transforming capacity and for the design of mutation-specific therapeutic approaches.

scholarly journals Secondary mutations as mediators of resistance to targeted therapy in leukemia

Blood ◽  
2015 ◽  
Vol 125 (21) ◽  
pp. 3236-3245 ◽  
Author(s):  
Naval Daver ◽  
Jorge Cortes ◽  
Farhad Ravandi ◽  
Keyur P. Patel ◽  
Jan A. Burger ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Tyrosine Kinase ◽  
Small Molecule ◽  
Myeloid Leukemia ◽  
Point Mutations ◽  
Kinase Domain ◽  
Lymphocytic Leukemia ◽  
Tyrosine Kinase Domain ◽  
Flt3 Inhibitors ◽  
Kinase Domain Mutations

AbstractThe advent of small molecule-based targeted therapy has improved the treatment of both acute and chronic leukemias. Resistance to small molecule inhibitors has emerged as a common theme. The most frequent mode of acquired resistance is the acquisition of point mutations in the kinase domain. FLT3 inhibitors have improved response rates in FLT3-mutated acute myeloid leukemia (AML). The occurrence of the ATP-binding site and activation loop mutations confers varying degrees of resistance to the individual FLT3 inhibitors. Second-generation FLT3 inhibitors such as crenolanib may overcome the resistance of these mutations. Furthermore, nonmutational mechanisms of resistance such as prosurvival pathways and bone marrow signaling may be upregulated in FLT3 inhibitor-resistant AML with secondary kinase domain mutations. More recently, point mutations conferring resistance to the Bruton tyrosine kinase inhibitor ibrutinib in chronic lymphocytic leukemia, arsenic trioxide in acute promyelocytic leukemia, and the BH3-mimetic ABT199 in lymphoma have been identified. In chronic myeloid leukemia, the emergence of tyrosine kinase domain mutations has historically been the dominant mechanism of resistance. The early identification of secondary point mutations and their downstream effects along with the development of second- or third-generation inhibitors and rationally designed small molecule combinations are potential strategies to overcome mutation-mediated resistance.

Point mutations in the juxtamembrane domain of FLT3 define a new class of activating mutations in AML

Blood ◽  
2006 ◽  
Vol 107 (9) ◽  
pp. 3700-3707 ◽  
Author(s):  
Carola Reindl ◽  
Ksenia Bagrintseva ◽  
Sridhar Vempati ◽  
Susanne Schnittger ◽  
Joachim W. Ellwart ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Apoptotic Cell ◽  
Point Mutations ◽  
Kinase Domain ◽  
Structural Basis ◽  
Tyrosine Kinase Domain ◽  
Juxtamembrane Domain ◽  
Downstream Target ◽  
Activating Mutations ◽  
New Class

In acute myeloid leukemia (AML), two clusters of activating mutations are known in the FMS-like tyrosine kinase-3 (FLT3) gene: FLT3-internal tandem duplications (FLT3-ITDs) in the juxtamembrane (JM) domain in 20% to 25% of patients, and FLT3 point mutations in the tyrosine-kinase domain (FLT3-TKD) in 7% to 10% of patients, respectively. Here, we have characterized a new class of activating point mutations (PMs) that cluster in a 16-amino acid stretch of the juxtamembrane domain of FLT3 (FLT3-JM-PMs). Expression of 4 FLT3-JM-PMs in interleukin-3 (IL-3)-dependent Ba/F3 cells led to factor-independent growth, hyperresponsiveness to FLT3 ligand, and resistance to apoptotic cell death. FLT3-JM-PM receptors were autophosphorylated and showed a higher constitutive dimerization rate compared with the FLT3-wild-type (WT) receptor. As a molecular mechanism, we could show activation of STAT5 and up-regulation of Bcl-x(L) by all FLT3-JM-PMs. The FLT3 inhibitor PKC412 abrogated the factor-independent growth of FLT3-JM-PM-expressing cells. Compared with FLT3-ITD and FLT3-TKD mutants, the FLT3-JM-PMs showed a weaker transforming potential related to lower autophosphorylation of the receptor and its downstream target STAT5.Mapping of the FLT3-JM-PMs on the crystal structure of FLT3 showed that these mutations reduce the stability of the autoinhibitory JM domain, and provides a structural basis for the transforming capacity of this new class of gain-of-function mutations of FLT3.

Point Mutations Found in the Juxtamembrane Domain of FLT3 Define a New Class of Activating Mutations in AML.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4388-4388
Author(s):  
Carola Reindl ◽  
Ksenia Bagrintseva ◽  
Susanne Schnittger ◽  
Joachim W. Ellwart ◽  
Katja Wenig ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Apoptotic Cell ◽  
Point Mutations ◽  
Kinase Domain ◽  
Structural Basis ◽  
Tyrosine Kinase Domain ◽  
Juxtamembrane Domain ◽  
Activating Mutations ◽  
New Class ◽  
Amino Acid Stretch

Abstract In acute myeloid leukemia (AML) FMS-like tyrosine kinase-3 (FLT3) has been shown to be mutated in about one third of patients. Until now, two distinct activating mutations are known: FLT3-length mutations (FLT3-LM) in the juxtamembrane (JM) domain in 20–25% and FLT3-point mutations in the tyrosine-kinase domain (FLT3-TKD) in 7–10% of patients. Here, we have characterized a new class of activating point mutations (PM) that cluster in a 16 amino acid stretch of the juxtamembrane domain of FLT3 (FLT3-JM-PM). Stable expression of four distinct FLT3-JM-PM in IL-3 dependent murine Ba/F3 cells led to factor-independent growth, hyperresponsiveness to FLT3-ligand and resistance to apoptotic cell death compared to FLT3-WT-expressing cells. As a molecular mechanism, we could show activation of STAT5 and upregulation of Bcl-x(L) by all FLT3-JM-PM. A selective FLT3-inhibitor, PKC412, was able to abrogate the factor-independent growth of FLT3-JM-PM. Mapping of the FLT3-JM-PM on the crystal structure of FLT3 showed that these mutations probably reduce the stability of the JM domain in the autoinhibitory conformation, and provide a structural basis for their transforming capacity. Our results show that point mutations in the autoinhibitory JM domain represent a new class of gain-of-function mutations able to activate the transforming potential of FLT3.

FLT3-ITD and tyrosine kinase domain mutants induce 2 distinct phenotypes in a murine bone marrow transplantation model

Blood ◽  
2005 ◽  
Vol 105 (12) ◽  
pp. 4792-4799 ◽  
Author(s):  
Rebekka Grundler ◽  
Cornelius Miething ◽  
Christian Thiede ◽  
Christian Peschel ◽  
Justus Duyster
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Tyrosine Kinase ◽  
Marrow Transplantation ◽  
Point Mutations ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Murine Bone Marrow ◽  
Juxtamembrane Region ◽  
Transplantation Model

Abstract Activating mutations of the Fms-like tyrosine kinase 3 (FLT3) receptor are the most common genetic alteration in acute myeloid leukemia (AML). Two distinct groups of FLT3 mutations are found: internal tandem duplications (ITDs) of the juxtamembrane region and point mutations within the tyrosine kinase domain (TKD). Recently, point mutations within the activation loop of FLT3 have also been described in childhood acute lymphoblastic leukemia (ALL). FLT3-ITD has been shown to induce a myeloproliferative syndrome in a murine bone marrow transplantation model. The phenotype of FLT3-TKD in mice has not yet been investigated. We transduced murine bone marrow with retrovirus-expressing FLT3-TKD mutants or FLT3-ITD and transplanted these cells into lethally irradiated mice. Mice that received a transplant of FLT3-ITD developed an oligoclonal myeloproliferative disease as previously described. In contrast, FLT3-TKD mutants induced an oligoclonal lymphoid disorder with longer latency and distinct hematologic manifestations: importantly, induction of the lymphoid phenotype was not due to a low number of transplanted cells. The lymphoid manifestation and longer latency of FLT3-TKD compared with FLT3-ITD mutants together with the lack of influence of FLT3-TKD mutations on the clinical outcome of patients with AML suggest differences in cell signaling between FLT3-TKD mutants and FLT3-ITDs. Indeed strong signal transducers and activators of transcription 5 (STAT5) activation could only be demonstrated for FLT3-ITDs. (Blood. 2005;105:4792-4799)

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