FMS-Like Tyrosine Kinase 3 in Normal Hematopoiesis and Acute Myeloid Leukemia - 《stemcells》干细胞学杂志干细胞之家



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作者：Bertrand W. Parcellsa, Alan K. Ikedaa, Tiffany Simms-Waldripa, Theodore B. Moorea, Kathleen M. Sakamotoa,b,c作者单位：a Division of Hematology/Oncology, Department of Pediatrics, Gwynne Hazen Cherry Memorial Laboratories, Mattel Childrens Hospital, Jonsson Comprehensive Cancer Center, Los Angeles, California, USA;b Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of Calif
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      【摘要】
   Ligand-mediated activation of the FMS-like tyrosine kinase 3 (FLT3) receptor is important for normal proliferation of primitive hematopoietic cells. However, activating mutations in FLT3 induce ligand-independent downstream signaling that promotes oncogenesis through pathways involved in proliferation, differentiation, and survival. FLT3 mutations are identified as the most frequent genetic abnormality in acute myeloid leukemia and are also observed in other leukemias. Multiple small-molecule inhibitors are under development to target aberrant FLT3 activity that confers a poor prognosis in patients. 5 q4 t1 H3 f, _8 U2 H+ s8 u
      【关键词】 FMS-like tyrosine kinase Hematopoiesis Acute myeloid leukemia Internal tandem duplication Small molecule inhibitor
   INTRODUCTION
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The hematopoietic system is organized into a strict hierarchy that sustains a steady-state production of more than one million blood cells per second . The hematopoietic system has evolved to offset the cellular processes of differentiation and proliferation to limit opportunities for oncogenic mutations. However, in spite of the molecular and systemic checks and balances, malignancies arise in the hematopoietic system as various forms of leukemia.
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Acute myeloid leukemia (AML) is a heterogeneous malignant disorder of myeloid precursor cells with clinical features of increased blasts in the blood and bone marrow . Mutations leading to the constitutive activation of the FMS-like tyrosine kinase 3 (FLT3) receptor, also known as fetal liver kinase 2 and human stem cell kinase 1, have been identified as the most frequent genetic disorder in AML and also confer a poor clinical prognosis. This review examines the function of normal FLT3 signaling and the aberrant downstream signaling caused by FLT3 mutations that evade normal control mechanisms. Subsequently, the clinical implications associated with this oncogenic pathway and the potential for targeted therapy are considered.  b' y0 [+ `. Q9 E  ~7 b0 p& `
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FLT3 IN NORMAL HEMATOPOIESIS

FLT3 Ligand. T1 |$ d% L' p  H9 }$ S
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Several cytokines in the bone marrow act through stem cell-specific or progenitor cell-specific receptors to regulate the capacity of immature hematopoietic cells to potentiate downstream multilineage expansion. The FLT3 ligand (FL) regulates early hematopoiesis by stimulating the FLT3 signal transduction pathway. FL is a type I transmembrane protein belonging to a small family of cytokines including stem cell factor and macrophage colony-stimulating factor (CSF) .
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FLT3 Receptor& V% @9 G7 }1 b% ~

FL associates with the transmembrane receptor FLT3, a member of the type III receptor tyrosine kinase (RTK) subfamily that includes c-KIT, c-FMS, and platelet-derived growth factor (PDGF) /ß  (Fig. 1).
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Figure 1. Structure of the FLT3 receptor. Abbreviations: FLT, FMS-like tyrosine kinase 3; ITD, internal tandem duplication.

FLT3 Receptor Expression
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The narrow range of cells expressing the FLT3 receptor primarily determines the specificity of FL signaling. FLT3 expression in the bone marrow is restricted to CD34  cells and the subset of dendritic precursor cells. FLT3 expression is correlated with "short-term" reconstituting HSCs, the Lin Sca-1 c-Kit  FLT3  compartment .7 i% |0 H3 E$ ?

Synergy of FL with Other Cytokines. P0 h' f. a+ B! R/ d- x2 T$ l
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Experimental evidence indicates that FL signals synergistically with other growth factors to promote proliferation in early progenitor cells of the myeloid and lymphoid lineages. FL-mediated signaling is highly dependent on related growth factors such as interleukin 3 (IL-3), granulocyte colony-stimulating factor (G-CSF), colony-stimulating factor-1 (CSF-1), and granulocyte macrophage colony-stimulating factor (CM-CSF), because FL inefficiently promotes proliferation as a single cytokine in vitro ., V9 g, U" Z1 y

Normal FL signaling is also associated with proliferation of the lymphoid lineage. In fact, targeted disruption of FL in mice led to a particular reduction of lymphoid precursor cells within the general reduction of primitive hematopoietic cells. FL¨C/¨Ccaused impairment of the immune system by reducing numbers of pro-B cells, dendritic cells (DCs), and natural killer cells .
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FLT3 Receptor Signaling8 g/ Y6 ?* c# l5 Z+ e0 ^0 d5 ~

FL binds to the FLT3 receptor to induce formation of a homodimer in the plasma membrane. The dimer couples cytoplasmic domains thereby enabling transphosphorylation of specific tyrosine residues, likely Tyr-589 and Tyr-591, on the JM domain . The FLT3 signal-transduction pathways are not conclusively mapped, yet current understanding of downstream pathways provides molecular support for its vital role in proliferation and apoptosis of primitive hematopoietic cells.

Despite the observed molecular effects of the FLT3 pathway, knockout mice have relatively stable hematopoiesis . Although these results indicate the presence of functional redundancies between hematopoietic growth factors, they do not detract from the role of FLT3 in differentiation and proliferation of early progenitor cells of the myeloid and lymphoid lineages.- B7 n- D8 d/ G& r. _
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FLT3 IN LEUKEMIA' [+ V) ~3 m: a8 Z
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Self-renewal and growth factor-independent proliferation are two important traits for oncogenesis. The involvement of FLT3 in proliferation of highly undifferentiated hematopoietic cells suggests the oncogenic potential of this signaling pathway. Clinical and experimental evidence both indicate that FLT3 is a proto-oncogene with the capacity to enhance survival and proliferation of leukemia blast cells. Wild type FLT3 is expressed in a wide range of hematopoietic malignancies, including acute lymphoid leukemia and mixed lineage leukemia; most notably, it is expressed in 70%¨C100% of AML . Two types of mutations have been attributed to the deregulated FLT3 receptor.

FLT3 Internal Tandem Duplication Mutation
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An in-frame internal tandem duplication (ITD) mutation in the JM domain of the FLT3 receptor correlates with the highest frequency of FLT3 related AML cases. Clinical studies identify the FLT3-ITD mutation in 17%¨C26% of AML cases .
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The ITD mutation causes constitutive activation of the FLT3 receptor. The JM region of many RTKs acts through various mechanisms to regulate the kinase domain. The crystal structure of the normal FLT3 receptor offers direct insight into the mechanism used by the JM domain to regulate catalytic activity of the kinase domain and suggests how the ITD disrupts this mechanism. FLT3 activity occurs when normal phosphorylation of specific tyrosine residues prevents the JM domain from folding properly to induce autoinhibition . The ITD insertion generally occurs near the JM hinge region and may offset the JM orientation thereby causing a "leaky" autoinhibition of catalytic activity.# a/ ^* K& }, M

There is no correlation between the size of the insertional mutation and the degree of autophosphorylation . Such conflicting results may be reconciled by further analysis into the ratio of wild type to mutant receptors on the plasma membrane. This ratio may affect the degree of autophosphorylation because the FLT3-ITD receptor can homodimerize with mutant receptors or heterodimerize with wild-type receptors independent of the ligand." I, V* ^. |$ L1 E
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Single-Amino Acid Mutations in FLT3

Missense point mutations in the kinase domain can also confer constitutive activation of the FLT3 receptor. The most common activating point mutation is the substitution of tyrosine for aspartic acid at position 835 within the activation loop of the kinase domain. Point mutations at other positions, such as 836 or 841, have also been associated with FL-independent activation .4 e) d' U' ?; q! {+ \; F6 w5 {
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FLT3 Mutant Signaling5 p9 Z0 P% U* M
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Parallels between the FLT3 receptor and related RTKs suggest that activating mutations disrupt an autoinhibitory mechanism that is critical for maintaining the inactive conformation of the kinase domain. The mutant receptor activates effector proteins to mediate proliferation and survival and blocks differentiation through ligand-independent autophosphorylation. Identifying molecules of the mutant signaling pathway offers insight into its role in the pathogenesis of leukemia (Fig. 2).' `. g( q( l: P: A7 J- Q: o
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Figure 2. Signal transduction pathways downstream of FMS-like tyrosine kinase-3 receptor activation. Abbreviations: C/EBP, CCAAT/ enhancer-binding protein ; ERK, extracellular-signal regulated kinase; MAP, mitogen-activated protein; PI-3 kinase, phosphatidylinositol 3-kinase.: A  v) z( ?9 [' S0 ~; H

Aberrant stimulation of proteins that confer a proliferative advantage was first identified in mutant-FLT3 myeloid leukemia cells. In vitro, the 32D mouse myeloid cell line harboring the ITD-mutation showed factor-independent proliferation and resistance to radiation-induced apoptosis .

Constitutively phosphorylated STAT5 has been observed in primary AML blasts and in immortalized cell lines Ba/F3 and 32D that express the mutated FLT3 receptor . It remains unclear whether mutant FLT3 receptors promote leukemogenesis by increasing quantitative signaling of normal effector proteins or by causing qualitative differences in downstream targets.
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STAT5 is known to activate PIM-1, and RNA microarray data identified a consistent increase in PIM-1 expression in FLT3-ITD cells . Quantitative PCR further implicated PIM-1 as a target of aberrant STAT5 expression by correlating a 10-fold decrease in its expression with FLT3 inhibition. PIM-1 is normally induced by a number of FL-related cytokines, including G-CSF and IL-3, to increase cell mitogenesis and survival. The effect of PIM-1 activity occurs through phosphorylation of a diversity of substrates including Cdc25A, which is key to cell cycle progression, and Bad, which blocks proapoptotic signaling. PIM-1 has also been reported to cooperate within antiapoptotic pathways in chronic myeloid leukemia (CML) cell lines.
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FLT3 and Differentiation4 A) T' \2 j$ }

FLT3 activity may also regulate differentiation pathways. Differentiation is tightly associated with the loss of proliferative capacity and increased propensity toward apoptosis. Normal myeloid progenitor cells proceed along a differentiation gradient to arrive at a terminally differentiated cell type with a limited lifespan. Blocking differentiation has been identified as an important mechanism for cancer progression. The preferential expression of FLT3 in primitive hematopoietic cells suggests its role in regulating differentiation. FL activation of 32D cells transfected with wild-type FLT3 mitigated their progression toward differentiated neutrophils but could not induce a complete block .! t  V# d. d+ g
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However, RGS2 mRNA, a regulator of G-protein signaling, was observed to be significantly repressed in the majority of primary AML bone marrow samples that harbor the FLT3-ITD mutation compared with AML samples lacking the mutation . Several myeloid cell lines have been shown to induce RGS2 during granulocytic differentiation, and RGS2 overexpression in 32D cells expressing FLT3-ITD overcomes the block to differentiation. The study suggests that FLT3-ITD signaling represses differentiation to some degree in AML cases, depending on the cellular context.

FLT3 Phosphatases3 z6 R/ W) G5 ^" P6 Z
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The constitutive activation of FLT3 may be further promoted by suppression of protein-tyrosine phosphatases (PTPs). The SH2 domain-containing PTPs SHP-1 and SHP-2 are commonly involved in regulating cytokine- and growth factor-mediated signaling pathways . SHP-1 loss of function led to factor-independent growth. Increased phosphatase activity normally occurs in response to kinase activation, yet the observed SHP-1 suppression common to RTK-mediated malignancies suggests the importance of overcoming PTP activity to shift the phosphorylation balance toward a proliferative advantage. SHP-1 also regulates signaling of related hematopoietic receptors, and its suppression by FLT3 may induce synergistic effects by sensitizing cells to multiple growth factors.

FLT3 and In Vivo Models of Leukemia% l. X' f5 l( F, Y, ~; u9 ~- h

At the molecular level, FLT3 appears to recruit many proteins involved in proliferation, self-renewal, and anti-apoptosis. The expression profiles of mutant FLT3 cell lines support its association with leukemogenesis by identifying a number of genes involved with growth and survival. However, the diversity of protein function and the redundancies in cellular processes prevent clear correlations between proteins and their function.

FLT3 mutations are insufficient to induce leukemia blasts in vivo . The association of the PML/ RAR mutation with block to differentiation suggests that although mutant FLT3 may effect differentiation, transformation depends on a more potent mechanism. The block to differentiation may be a critical limitation for leukemogenesis through aberrant FLT3 signaling.. }  U% u" }+ j+ x! l, ^

Nevertheless, these studies are critical to implicating the mutated FLT3 receptor in leukemogenesis. As a single mutation, FLT3 induces a myeloproliferative phenotype, and primary AML cells expressing the FLT3-ITD receptor engraft into NOD/SCID mice with greater efficiency that those lacking the mutation .4 g; u/ F, c5 d; r
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Clinical Implications of FLT3 Mutations in AML/ F' J7 }  E4 C. J/ |
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Substitution mutations in the tyrosine kinase domain (TKD) and insertional mutations in the JM domain of FLT3 represent the most frequent genetic abnormality associated with AML. Both mutations lead to constitutively active FLT3, although studies indicate that each mutation presents unique clinical features.2 o; d$ ]* g0 o7 f; I9 m
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The FLT3-ITD mutation is recognized at diagnosis by leukocytosis, with the mean white blood cell (WBC) count typically elevated to levels significantly higher than that of patients without the mutation .
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Multiple studies indicate that FLT3-ITD mutations confer a poor prognosis in AML patients less than 60 years of age .! I( e% J* n1 A( ?" e
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Multiple studies used PCR to correlate high ratios of mutant to wild-type FLT3 with decreased overall survival . This provides evidence that FLT3 expression levels significantly affect prognosis and relapse. This suggests that the pathway exerts a strong influence on leukemia progression. However, the heterogeneity in AML blast gene expression and the notable fraction of AML patients that lose the FLT3-ITD mutation in relapse indicate that multiple factors determine disease progression and that FLT3-ITD should not be exclusively used as a marker for MRD.

In pediatric cases, the ITD mutation provides a more negative and independent prediction of prognosis. Data from six combined pediatric studies, which examined 461 pediatric AML patients, identified a 19% survival rate for cases associated with FLT-ITD compared with a 58% survival rate for patients with wild-type FLT3 receptors .- ^6 A/ L- F3 ~  Z! w0 {
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The clinical pathogenesis of FLT3-TKD expressing AML is less understood than the FLT3-ITD due to its lower frequency in patients, which limits the number of statistically significant conclusions . Studies have also identified a higher frequency of FLT3-TKD mutations in patients with MLL duplications or a double-stranded break in the MLL gene. Future clinical studies must examine larger AML populations to achieve significant insight into potential effects of FLT3-TKD mutations.: Q: b* [- @- K9 E1 |

FLT3 INHIBITORS( Q- v1 Z2 I8 I# }9 i/ l& Z
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The fundamental principle of small-molecule therapy is to inhibit specific RTKs involved with tumorigenesis while minimizing the inhibition of normal cellular signaling to limit toxicity. The recognition of small-molecule inhibitors as therapy for deregulated RTKs emerged in the wake of the clinical success of imatinib mesylate in CML. CML progresses almost exclusively through the constitutively active bcr-abl fusion protein tyrosine receptor. Its robust response to imatinib provided proof of principle for the potential efficacy of targeted therapy . Preliminary clinical data from therapeutic targeting of the FLT3 mutations in AML suggests that small-molecule inhibitors may effectively complement traditional therapy regimens to treat a broader range of malignancies.

FLT3 is an appropriate candidate for targeted therapy because it is expressed in many hematopoietic malignancies, it is the most frequent molecular abnormality in AML, it confers a poor prognosis, and its signaling cascade has been implicated in multiple tumorigenic pathways. Currently, there are several small-molecule therapies at various stages of development that target mutant forms of the FLT3 receptor (Table 1). All of the FLT3 inhibitors being studied are heterocyclic compounds with a purine ring-like subunit that competitively inhibits ATP binding to FLT3 . Data on related receptors suggests that the molecules inhibit activity by entering into the ATP binding pocket through an induced fit or lock-and-key manner, although the specific mechanism may vary between inhibitors. A brief summary of the molecules is given below.

Table 1. Small-molecule tyrosine-kinase inhibitors

The compounds AG1295 and AG1296 were the first to be identified as inhibitors of cells harboring the FLT3-ITD mutation through a similar screening process used to identify imatinib .7 l" f+ F. H; v  n) j+ Y

SU5416 was the first indolinone compound to be identified as a potential inhibitor of FLT3 activity. It has also been shown to inhibit vascular endothelial growth factor 2 (VEGF2) and c-KIT .1 M, d! `' C3 i/ o
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The indolinone derivative PKC412 (4'-N-benzoylstaurosporine) was originally identified as an inhibitor of protein kinase C . The drug showed measurable activity, evidenced by a 50% reduction in peripheral blast count in 14 patients, a greater than 2-log reduction in peripheral blast count in seven of these patients, and a 50% reduction in bone marrow blast counts in six patients. PKC412 was generally well tolerated.

The compound SU11248 is another indolinone derivative shown to inhibit FLT3, as well as VEGF2, PDGFß, and fibroblast growth factor 1 (FGF1) . One-third of patients exhibited a significant decrease in FLT3 phosphorylation, although a minority of patients experienced gastrointestinal or cardiac symptoms of toxicity.

MLN518 (CT53518) is a piperazinyl quinazoline that inhibits growth of FLT3-ITD-transformed cells in vitro and in vivo .

The indolocarbazole derivative CEP-701 was originally identified as an inhibitor of TrkA tyrosine kinase . Most responses were observed by reduced peripheral blast counts; however, one patient showed a 95% reduction of bone marrow blasts before relapse 3 months later. Minimal toxicity was observed.

Komeno et al. recently identified Ki23819 as a potent inhibitor of mutant FLT3. The compound suppressed proliferation of MV4¨C11 cells at IC50 of 1 nM . These preliminary in vitro results suggest promising translation into clinical inhibition of mutant FLT3, but the compound requires further study in mouse models. To summarize, most clinical studies with FLT3 inhibitors have demonstrated a moderate response, more evident in the peripheral blood than in bone marrow.
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Resistance, C6 t1 g* g( p# X/ i( f( {* H
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The development of small-molecule inhibitors is widely encouraged within the medical community because it offers an approach to treat cancer with relatively modest toxicity. Yet the targeting specificity that bestows a clinical advantage to this therapy may also be a critical flaw. The sensitivity of the compounds to the FLT3 structure confers not only specificity but also susceptibility to minor structural changes that are induced by mutation. The high mutational load that most tumors support during progression indicates a high probability of drug-resistant subclones. A mathematical model that closely recapitulates clinical findings from CML predicts that most leukemias will contain cells resistant to multiple molecular inhibitors at the time of diagnosis .

Acquired resistance to small-molecule inhibition has been identified in AML blasts harboring constitutively active FLT3 receptors . These mutations recovered sensitivity to PKC412, SUS5614, and a CEP-701-like compound at higher concentrations in vitro, yet increased drug concentrations may not translate into a successful method for circumventing resistance in clinical AML. Many FLT3 inhibitors were originally identified as inhibitors of other RTKs and became directed specifically against FLT3 because the receptor showed inhibition at the lowest concentration threshold. If mutations can raise the concentration threshold to a level at which other RTKs respond, then normal cells may experience significant cytotoxicity, and clinical side effects may become severe. Evidence of acquired resistance does not invalidate the clinical potential of targeted therapy but suggests that curative treatment must extend beyond a single agent.

Data from in vitro and in vivo experiments offers promising strategies for combination therapy. The synergistic effects of SU11657 and all-trans retinoic acid induced rapid regression in an APL mouse model . The treatment regimen examined in this study is currently being applied to a clinical trial. The diversity of potential combination therapies and the significance of sequence in drug administration indicates that substantial optimization studies must be conducted before treatment regimens are designed for specific genetic abnormalities.1 E8 [: f# Q8 J
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Many of the aforementioned compounds may translate into effective treatments for cancer, yet it is possible that they will only provide a selective force for highly resistant clones. One particular point mutation in the FLT3 receptor, Gly-697, poses a significant challenge because its structure confers resistance to multiple compounds, including PKC412, SU5614, and a molecule similar to CEP-701 . Similar to the CML blast crisis, AML blast cells that harbor FLT3 mutations are likely to have additional mutations that may drive tumor progression while showing no response to FLT3 inhibition. Ideally, the response rate for FLT3 inhibition will compare to the 30% response to imatinib during CML blast crisis. Identification of new molecules will be key to preventing resistance in the future. Combining compounds that inhibit various proteins within the signaling pathway may also improve the efficacy of treatment.

ACKNOWLEDGMENTS

B.W.P. is supported by the Skirball Foundation (awarded to T.B.M.). K.M.S. is a Scholar of the Lymphoma and Leukemia Society and is supported by the NIH (CA108545  , HL 75826, RHL083077A), American Cancer Society (RSG-99-081-04-LIB), Department of Defense (CM050077), and the Diamond-Blackfan Anemia Foundation. Both T.B.M. and K.M.S. are funded by the UCLA Jonsson Comprehensive Cancer Center.

DISCLOSURES

The authors indicate no potential conflicts of interest.  a6 e+ M: v0 Y6 T" c
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