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Mutations in tyrosine kinase and tyrosine phosphatase and their relevance to the target therapy in hematologic malignancies Ni Zhu‡,1, Haowen Xiao‡,1,2, Li-Mengmeng Wang1, Shan Fu1, Chan Zhao3 & He Huang*,1

ABSTRACT Protein tyrosine kinases and protein tyrosine phosphatases play pivotal roles in regulation of cellular phosphorylation and signal transduction with opposite functions. Accumulating evidences have uncovered the relevance of genetic alterations in these two family members to hematologic malignancies. This review underlines progress in understanding the pathogenesis of these genetic alterations including mutations and aberrant expression and the evolving protein tyrosine kinases and protein tyrosine phosphatases targeted therapeutic strategies in hematologic neoplasms.

The first description of enzymatic phosphorylation of proteins was reported by Eugene P Kennedy nearly 60 years ago [1] , followed by the study of Tony Hunter and colleagues who discovered protein tyrosine kinases (PTKs) in 1979 [2] . For the last three decades, regulation of protein tyrosine phosphorylation has been proved to play important roles in signal transduction of proliferation, differentiation, adhesion, metabolic homeostasis and programmed death of eukaryotic cells [3] . PTKs participate in phosphorylation, which is reversed by protein tyrosine phosphatases (PTPs), namely, dephosphorylation. Dysregulation of protein tyrosine phosphorylation caused by either gene mutations or aberrant expression of PTKs or PTPs, which leads to abnormal biological functions mainly including excessive cell proliferation, impaired cell differentiation and dysregulation of cell apoptosis, has been revealed to be involved in the pathological process of cancer. Depending on the important roles, both PTKs and PTPs play in malignancies, the corresponding target therapy has paved way in treating cancer successfully. Precisely designed kinase inhibitors have been employed in lung cancer [4] , breast cancer [5] , gastrointestinal cancer [6] and leukemia [7] . Advanced understanding of phosphorylation regulation in cancer prompts novel target therapeutic strategies. This review focuses on the genetic alterations including mutations and aberrant expression of PTPs and PTKs and their relevance to the target therapy in hematologic malignancies.

KEYWORDS 

• genetic alterations • hematologic malignancies • protein tyrosine kinases • protein tyrosine phosphatases • target

therapy

Function of PTKs & PTPs PTKs and PTPs regulate downstream signal pathway by phosphorylation and dephosphorylation, which are supposed to be the most important way of intracellular signal regulation, respectively in the opposite directions to achieve physiological or pathological states. The common signal Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, PR China 2 Department of Haematology, Guangzhou Liuhuaqiao Hospital, Guangzhou, Guangdong Province, PR China 3 Department of Paediatrics, Jinhua Central Hospital, Jinhua, Zhejiang Province, PR China *Author for correspondence: Tel.: +86 571 8723 6706; Fax: +86 571 8723 6562; [email protected] ‡ Authors contributed equally 1

10.2217/FON.14.280 © 2015 Future Medicine Ltd

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Review  Zhu, Xiao, Wang, Fu, Zhao & Huang pathways include PI3K and PLC-γ relating to apoptosis. PI3K takes part in resisting apoptosis by phosphorylating AKT in hematologic neoplasms. On the contrary, PLC-γ phosphorylates protein kinase C (PKC), which will finally activate NF-κB that promotes apoptosis. On the other hand, PTKs and PTPs regulate expression of particular genes or proliferation through JAK/STAT and Ras/MEK/ERK pathways. In addition, the regulation of cytoskeleton through β-catenin/E-cadherin pathway is supposed to be related to migration and invasion of cancer cells (Figure 1) [8] . Genetic alterations in PTKs in hematologic malignancies PTKs are known as a large family of enzymes that catalyze the phosphorylation of tyrosine residues. These enzymes play important roles in varieties of cellular activities and vital signal pathways. PTKs are divided into two classes, including receptor tyrosine kinases (RTKs) possessing an N-terminal extracellular domain, a single transmembrane domain and a C-terminal cytoplasmic domain (Figure 2) and non-RTKs, most of which are soluble intracellular proteins without a transmembrane domain [9] . RTKs, a group of high-affinity cell surface receptors for many polypeptide growth factors, PTKs

cytokines and hormones, have already been identified as approximately 20 different classes [10] . Most RTKs function in transmembrane signal process, genetic alterations of which have been reported to be associated with hematopoietic malignancies that have been indicated in Table 1. On the other hand, the non-RTKs (nRTKs) are responsible for signal transduction to the nucleus. nRTKs are cytoplasmic enzymes that can catalyze the phosphate group removing from ATP to a tyrosine residue of a protein, the main function of which is the regulation of the immune system, in activated T and B cells in the immune system [11] . Genetic alterations in the nRTK genes also have been indicated to be relevant to hematopoietic malignancies (Table 2) . ●●FLT-3

FLT-3, which belongs to FMS/KIT family, plays a role in the biology of early hematopoietic progenitor cells and is highly expressed in both acute myelocytic leukemia and acute lymphocytic leukemia [12] . The major somatic mutations include internal tandem duplications (ITDs) that occur in exons 14 and 15 [13] and other point mutations within the activation loop of the tyrosine kinase domain (FLT3/TKD mutations) [14] . ITD mutations are detectable in about 20% of acute myeloid leukemia (AML) patients

PTPs Gene alterations

PI3K

Ras

PLCγ

PKC AKT

β-catenin/E-cadherin

JAK/STAT MEK1/2

MAPK pathway

IKK Cytoskeleton regulation Anti-apoptosis

NF-κB

Apoptosis

ERK1/2

Gene expression

Proliferation

Figure 1. The main signal transduction pathways involved in protein tyrosine kinases and protein tyrosine phosphatases relevant to hematopoietic neoplasms. PTK: Protein tyrosine kinase; PTP: Protein tyrosine phosphatase.

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Mutations in tyrosine kinase & tyrosine phosphatase 

Extracellular Class III

PDGFR

Class IV

FGFR

Class VII

TRK

Class IX

AXL

TM

Review

Intracellular

Intracellular kinase domain

TM

IgD

LRD

AB

Fn

Figure 2. The structures of protein tyrosine kinases involved in hematopoietic neoplasms. Receptor tyrosine kinases possess an N-terminal extracellular domain, a single transmembrane domain and a C-terminal cytoplasmic domain. AB: Acidic box; FGFR: FGF receptor; FN: Fibronectin III repeat; LRD: Leucine-rich domain; PDGFR: PDGF receptor; TM: Transmembrane domain.

and indicated a poor prognosis [15] . The FLT3 isoforms containing ITD mutations possessed oncogenic potential by downstream constitutively activation of RAS, STAT5 and MAPK pathway [16,17] . The TKD mutations are reported in approximately 7% of patients, which seems to incline to better prognosis [18] . It has been reported that FLT3/ITD+ patients had heavier leukocytosis and higher percentage of BM blast cells at diagnosis. The presence of an FLT3/ITD was the major factor predicting for relapse and disease-free survival and had an adverse effect on event-free survival and overall survival. However, the clinical impact of an FLT3/ITD may also vary between different cytogenetic entities [19] . Another retrospective analysis has revealed that FLT3/ITD adversely affected the outcome of hematopoietic transplantation in the same direction it does after chemotherapy [20] . FLT3/ITD led to increased relapse incidence and was associated with decreased leukemia-free survival. ●●C-KIT (CD117)

Another genetic mutation of RTKs reported is C-KIT (CD117) [21] . C-KIT is expressed in the progenitors of mast cells and is promoted by stem cell factor to regulate hematopoietic stem cells

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and derived mast cells [22,23] . Three major point mutations have been reported including Val560Gly, Asp816-Val and Asp816-Tyr, all of which occur in intracellular TKD of C-KIT [24–26] . There is also a report of exon 8 in-frame deletion plus insertion mutations that involve the loss or replacement of Asp419, a highly conserved codon located in the extracellular domain [27] . The activating KIT mutation in codon 816 is a character of systemic mastocytosis [25,28] . The constitutive activation of KIT kinase plays a pivotal role in the pathogenesis, diagnosis and target therapy of systemic mastocytosis [29] . The activating mutations of C-KIT represent the most frequently mutated target in adult core binding factor AML and indicate higher risk and shorter survival [30,31] . ●●C-FMS

The mutations of C-FMS, which is also named CSF1R are first reported by employing hybridization to allele-specific oligonucleotide probes in AML and myelodysplastic syndrome patients involving codon 969 and 301 [32,33] . However, other studies employing direct sequencing [34] or allele-specific restriction analysis [35] both failed to detect the mutations reported previously. Later Faisel et al. [36] presented mutations involving exons 6 and 9 without the definition of their

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Review  Zhu, Xiao, Wang, Fu, Zhao & Huang Table 1. Receptor protein tyrosine kinases relevant to hematopoietic neoplasms. Receptor PTKs RTK classes

Affected signaling pathways

Major cancer types

Gene alterations

PDGFR-α PDGFR-β C-FMS

III III III

PI3K, ERK1/2, STAT5 PI3K, STAT5, PLC-γ Not clear

CEL CML, CEL, myeloid neoplasm Leukemia cell lines

C-KIT

III

AKT, STAT5, ERK

FLT-3

III

RAS, STAT5, MAPK

Systemic mastocytosis, AML especially CBF-AML AML

FGFR-1 TRK-C AXL

IV III IX

PI3K/AKT, STAT5, PLC-γ, Notch pathway MAPK PI3K/AKT, ERK, NF-κB

SCLL AML CML, AML

Genetic rearrangement Genetic rearrangement Genetic rearrangement, point mutation Point mutations, deletions and overexpression internal tandem duplication, missense point mutation Genetic rearrangement Genetic rearrangement Overexpression

AML: Acute myeloid leukemia; CBF: Core binding factor; CEL: Chronic eosinophilic leukemia; CML: Chronic myeloid leukemia; FGFR: FGF receptor; PDGFR: PDGF receptor; PTK: Protein tyrosine kinase; SCLL: Stem cell leukemia–lymphoma syndrome.

pathological role in leukemogenesis. In addition, the fusion of RBM6 to CSF1R [37] and Y571D mutation [38] was detected in different cell lines. ●●PDGF receptors

Both PDGF receptors (PDGFRs) α and β are involved in mutations relevant to hematopoietic neoplasms. The genetic alteration of PDGFR-β was reported earlier than PDGFR-α with genetic rearrangement in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation [39] . The role of this TEL/PDGFR-β fusion gene in leukemogenesis has been elucidated that the receptor kinase was constitutively activated by enforced dimerization of TEL [40] . Since then, several different fusion genes of PDGFR-β have been reported in succession [41–48] . The ligand binding of PDGFR-β initiates PI3, STAT5 and PLC-γ signal pathways that will ultimately influence gene expression and modulate cell proliferation [49,50] . In addition, the fusion protein is reported to influence apoptosis by antagonizing the effects of TEL and ICSBP on PTPN13 transcription, which increases Fap1-dependent Fas resistance, in a manner that is independent of tyrosine kinase activity [51] . A study of PDGFR-α revealed the fusion with FIP1L1 (Fip1-like1) generated by an interstitial deletion on chromosome 4q12 [52] . The rearrangement is mostly reported in chronic eosinophilic leukemia, which is usually presented as idiopathic hypereosinophilic syndrome, eosinophilia-associated AML and lymphoblastic T-cell lymphoma [53] . The fusion product functions as constitutively activated tyrosine kinase and cooperates with IL-5-dependent signaling in driving abnormal eosinophil development evidenced

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in a mouse model [54] . The study of FIP1L1PDFGR-α expressed in human hematopoietic progenitors indicated a myeloproliferative phenotype via activation of multiple signaling molecules including PI3K, ERK1/2 and STAT5 [55] . Several different types of genetic rearrangements related to PDFGR-α have also been reported [56–59] . ●●FGFR-1

FGFR1, the somatic mutations of which have been specifically associated with stem cell leukemia-lymphoma (SCLL) syndrome that is also known as the 8p11 myeloproliferative syndrome, is one of the FGFR protein family members [60] . Varieties of genes fused to FGFR1 have been reported [61–65] . ZNF198-FGFR1, the most commonly reported rearrangement, induces a myeloproliferative neoplasm (MPN) phenotype in mice as well as activation of the downstream effector molecules PLC-γ, STAT5 and PI3K/AKT via expression in hematopoietic stem cell [66] . In addition, constitutive activation of Notch pathway is also reported to be involved in the etiology of SCLL recently [67] . ●●AXL

The RTK AXL was initially reported with oncogenic potential in chronic myeloid leukemia (CML) and chronic myeloproliferative disease [68] . AXL is overexpressed in AML associated with a poor prognosis and drug resistance by the binding with Gas6, which initiates activation of PI3K/AKT, ERK and NF-κB [69,70] . A recent study identified AXL as a novel PTK in B-cell chronic lymphocytic leukemia that appeared to function as a docking site for multiple non-RTKs and drive leukemic cell survival signals [71] .

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Mutations in tyrosine kinase & tyrosine phosphatase  ●●Eph receptors

The Eph receptors, the largest family of tyrosine kinases, were named after an erythropoietin-producing human hepatocellular carcinoma cell line, from which the first Eph receptor was identified in vitro [72] . Unlike other tyrosine kinases, Eph receptors exhibit the unique way of bidirectional signaling thus playing opposite roles in cellular progress [73] . Eph receptors are quiescent in normal postembryonic tissues thus they are used as markers of malignancies. Eph receptors often play conflicting roles, either as oncogenes or as tumor suppressors, in many different malignancies including solid tumors and hematological neoplasms [74] . Among these receptors, EPHA3 is aberrantly expressed in almost all types of hematological malignancies [75,76] . Low expression of EPHA3 was detected in patients with CML in the chronic phase. However, the expression markedly elevated in patients in the accelerated or blastic phases [77] . The evidence that EPHA3 was expressed on CD34 + CD38-CD123 + cells, which represented a population of leukemia stem cells, while less commonly expressed on other leukemic cell fractions has proposed EPHA3 as a novel target for leukemia stem cells [78] . ●●Anaplastic lymphoma kinase

The RTK, anaplastic lymphoma kinase (ALK), is expressed specifically in the nervous system. Genetic alterations of ALK have been reported in anaplastic large cell lymphoma (ALCL) [79,80] . The translocation creating a fusion gene comprising ALK and nucleophosmin is associated with approximately 60% ALCL patients. Another fusion gene comprising ALK and TPM3 was detected in a smaller fraction of ALCL patients. ●●Non-RTKs

The genetic alterations of non-RTKs involved in hematopoietic neoplasms have been recognized for years. Genetic rearrangement and overexpression of nRTKs are among the most common

Review

alterations. The most comprehensively explored is the fusion of B-cell receptor (BCR) to ABL1, which is detected in all patients with CML and in a significant fraction of Ph-positive patients with acute lymphocytic leukemia [81] . Several variants of the fusion protein have been reported [82] . The other kinase involved in genetic rearrangement is ARG (also named ABL-related gene or ABL2) [83,84] . The genetic arrangement of JAK2 was first detected in a T-cell childhood acute lymphoblastic leukemia patient with t(9;12)(p24;p13) chromosomal translocation [85] , followed by other reports in myeloid leukemia [86] , CML [87] and acute erythroid leukemia [88] . Additionally, a point mutation in JAK2 was discovered in the majority of Philadelphia chromosome-negative MPN patients [89] . This mutation, JAK2V617F, was found in patients with polycythemia vera, essential thrombocythemia and primary myelofibrosis [90] . JAK2V617F induced constitutive activation of downstream signaling through the JAK-STAT, the MAPK and the PI3K/Akt pathways that finally promoted proliferation of affected cells [91] . Genetic alterations in protein tyrosine phosphatases in hematologic malignancies On the contrary, PTPs are a group of enzymes that remove phosphate groups from phosphorylated tyrosine residues on proteins, involved in signal transduction pathways and cellular functions [92] . They are grouped into four families based on the amino acid sequences of their catalytic domains [93] . The most frequently explored are the class I cysteine-based PTPs that comprise classical PTPs, which include receptor PTPs, nonreceptor PTPs and the dual-specific protein phosphatases (DUSPs) characterized with both serine-/threonine- and tyrosine-specific protein phosphatase activities. Genetic alterations of PTPs, which are relevant to hematopoietic neoplasms, are all in class I family (Table 3) .

Table 2. Nonreceptor protein tyrosine kinases relevant to hematopoietic neoplasms. Nonreceptor PTKs

Major cancer types

Gene alterations

LCK ABL1 ARG JAK2

Lymphoblastic leukemia CML, Ph+ ALL AML ALL, CML, AEL

Genetic rearrangement, overexpression Genetic rearrangement Genetic rearrangement Genetic rearrangement, point mutation

AEL: Acute eosinophilic leukemia; ALL: Acute lymphoblastic leukemia; AML: Acute myeloid leukemia; CML: Chronic myeloid leukemia; PTK: Protein tyrosine kinase.

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Review  Zhu, Xiao, Wang, Fu, Zhao & Huang ●●Nonreceptor tyrosine protein tyrosine

phosphatases

Somatic mutations of PTPN11, which encodes the PTP SHP-2, have been detected mostly in juvenile myelomonocytic leukemia, however, relatively rare in myelodysplastic syndromes and AML [94,95] . Leukemia-associated PTPN11 mutations are missense and are predicted to result in a gain-of-function role of these mutations on SHP-2 catalytic activity by molecular modeling and functional data analysis. Evidence has been found that leukemia-associated PTPN11 mutations induce Ras-ERK pathway, which finally contributes to leukemogenesis [96,97] . A report of focal deletions detected in PTPN2 in a subset of patients with T-cell acute lymphoblastic leukemia provides genetic evidence for a putative tumor suppressor gene of PTPN2 in T-ALL [98] . The overexpression of PTPN22 in CLL is recently reported, which significantly inhibits antigen-induced apoptosis of primary CLL cells by blocking BCR signaling pathways that negatively regulates lymphocyte survival as well as positively regulates the antiapoptotic AKT kinase that provides a powerful survival signal [99] . PTPN7, also named hematopoietic

tyrosine phosphatase (HePTP), was first identified to be expressed exclusively in thymus and spleen [100] . The amplification and overexpression of PTPN7, with the ability to transform NIH 3T3 cells, were suggested as an important cofactor contributing to abnormal myeloid cell growth [101] . The MAP kinase ERK2 is defined as a specific substrate of PTPN7. However, the detailed signal pathway in leukemogenesis has not been defined yet. Interestingly, another study has reported lower expression of PTPN7 in children B-cell lymphoma, which may imply the potential functions of PTPN7 as both oncogene and tumor suppression gene [102] . ●●Receptor protein tyrosine phosphatases

& DUSPs

As to receptor PTPs, the hypermethylation and silencing of PTPRG [103] and PTPRO [104] were detected in cutaneous T-cell lymphoma and chronic lymphocytic leukemia, respectively. It has been elucidated that suppression of PTPRO by promoter methylation could contribute to the augmented phosphorylation and constitutive activity of its substrate BCR/ABL1 [105] . Loss of heterozygosity has been reported to be related

Table 3. Protein tyrosine phosphatases relevant to hematopoietic neoplasms. PTPs

Affected signaling pathways

Major cancer types

Gene alterations

PTPN11

Ras pathway

PTPN13

FAS resistance

PTPN22

AKT, BCR signaling

T-ALL Lymphoma leukemia Leukemia lymphoma Juvenile myelomonocytic leukemia, MDS, AML Multiple lymphoma CLL

Focal deletion Methylation

PTPN7

Not clear Jak/STAT, cytokine signaling pathway Not clear

Cutaneous T-cell lymphoma Lymphoma

Methylation

CLL Non-Hodgkin’s lymphoma

Methylation LOH

Nonreceptor PTPs PTPN2 PTPN6

Amplification downregulation Mutation

Methylation Overexpression

Receptor PTPs PTPRG

Not clear

PTPRK

β-catenin/E-cadherin complexes Bcr-abl1 EGFR endocytosis, dephosphorylation of PDGFR-β

PTPRO PTPRJ

LOH

AML: Acute myeloid leukemia; CLL: Chronic lymphoblastic leukemia; LOH: Loss of heterozygosity; MDS: Myelodysplastic syndrome; PTP: Protein tyrosine phosphatase; T-ALL: T-cell acute lymphoblastic leukemia.

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Mutations in tyrosine kinase & tyrosine phosphatase  to PTPRK [106] and PTPRJ [107] in lymphoma. Both are presented as putative tumor suppressor genes [108,109] , the inactivation of which induced by loss of heterozygosity, plays roles in neoplasia. The overexpression of PRL-3 [110] , DUSP7 [111] and MTMR6 [112] has been detected in myeloma and leukemia. On the other hand, the downregulation of DUSP2 (PAC-1), which induces constitutive activation of ERK, has been reported in acute leukemia [113] . Novel therapeutic targets to PTKs & PTPs in hematologic malignancies Since the constitutive activation of PTKs or the downstream signal pathways is the common mechanism in neoplasia, drugs inhibiting tyrosine kinases seem to be powerful in clinical therapy. Efforts have been made in exploring TKIs, which have been applied in treatment of hematologic malignancies and have got promising efficacy (Table 4) . ●●BCR-ABL1 inhibitors

Imatinib, which is among the most impressive inhibitors, targets leukemia cells by preventing BCR-ABL1 from phosphorylating subsequent proteins that initiate the signaling pathway necessary for development of disease. The positive detection of BCR-ABL1 in CML cells, which is however absent in normal blood cells, gives opportunities to the impressive effectiveness of imatinib. However, nearly 20% of patients could not achieve a complete cytogenetic response with others acquiring intolerable side effects or drug resistance. The resistance to imatinib prompted the study of mechanism involved and novel approaches to handle the resistance. Studies have provided evidence that the resistance is often associated with the reactivation of BCR-ABL1 signal transduction mainly due to mutations in the kinase domain [114] . Later, evolving generations of inhibitors that own higher potency have been designed including nilotinib and dasatinib [115] . Clinical trials have provided evidence that both nilotinib and dasatinib induce hematologic and cytogenetic responses in patients with CML or Ph-positive ALL resistant to imatinib [116,117] . A Phase III, randomized, open-label, multicenter clinical trial revealed that nilotinib was superior to imatinib in patients with newly diagnosed chronic-phase Ph-positive CML [118] . Similar studies investigating dasatinib also underlined the high efficacy and safety for the first-line treatment of chronic-phase CML [119] . Notably,

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Review

another orally bioavailable dual Src/Abl1 inhibitor, 200-times as potent as imatinib, with minimal inhibitory activity against PDGFR or C-KIT, bosutinib is demonstrated to be active in chronic-phase CML after imatinib and dasatinib and/or nilotinib therapy failure [120] . These novel inhibitors have brought the management of CML patients into a hopeful era. Despite the promising clinical results of advanced TKIs overriding most resistance, none could effectively target the gatekeeper mutation, T315I, which disrupts the binding of imatinib to the ATP-binding pocket of ABL1 [121] . The next generation of TKIs make efforts on overriding the T315I mutation, which may provide opportunities for relapsed patients carrying this mutation. The pan-BCR-ABL1 inhibitor ponatinib has achieved high efficacy in heavily pretreated patients with Ph-positive leukemia with resistance to TKIs, including patients with the BCR-ABL1 T315I mutation, other mutations or no mutations [122] . A recent Phase II trial revealed promising response rates regardless of disease stage or mutation status [123] . Other inhibitors, including DCC-2036 [124] and HG-7-85-01 [125] , are also in research. ●●FLT3 inhibitors

FLT3 inhibitors, another category of comparable TKIs that have been explored passionately currently, mostly inhibit FLT3 activity by competing with ATP for binding to the ATP-binding pocket of the TKD [126] . More than 20 small molecule inhibitors against FLT3 have been reported, eight of which have been evaluated in clinical trials, including tandutinib, sorafenib, sunitinib, midostaurin, lestaurtinib, KW-2449, quizartinib and crenolanib (Table 5) . These clinical trials have demonstrated the potential efficacy of FLT3 inhibitors in AML patients. However, these agents are not specified as first-line treatment yet. Most responses are limited to hematological improvement with no more than 40% complete remission while applying alone. Furthermore, these inhibitors show efficacy in patients without FLT3 mutations, the majority of which is restricted to reduction in blast counts, which is supposed as results of the multikinase activities. Although clinical trials have revealed the initial responses of FLT3 inhibitors in FLT3ITD-positive patients, or even negative patients, subsequent relapse often occurs due to acquisition of secondary FLT3 TKD mutations, mainly

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Review  Zhu, Xiao, Wang, Fu, Zhao & Huang Table 4. Therapeutic targets to protein tyrosine kinases. Tyrosine kinase inhibitors

Target genes

Bosutinib Crizotinib Crenolanib Dasatinib Dovitinib Imatinib Nilotinib Pazopanib Ponatinib Quizartinib Regorafenib Ruxolitinib Sunitinib Sorafenib Tandutinib Vandetanib

SRC-ABL1 ALK FLT3 ABL1, PDGFR,KIT FGFR ABL1, PDGFR, KIT,FLT3 ABL1, PDGFR,KIT PDGFR,KIT FLT3, PDGFR, FGFR,BCR-ABL1 FLT3, PDGFR,KIT PDGFR,KIT JAK2 KIT, PDGFR,C-FMS,FLT3 PDGFR, KIT,FLT3 PDGFR, KIT,FLT3 FGFR

FGFR: FGF receptor; PDGFR: PDGF receptor.

reported at residues D835 and F691, which is paralleled to what happened to BCR-ABL1 inhibitors [137] . Despite the relatively low CR rate, the emergence of relapses has appeared to be a more serious problem. Previous studies have shown that the addition of chemotherapy failed to improve the relapses since no prolonged survival was observed [138] . The emergence of TKD mutations suggests that novel FLT3 inhibitors that harbor the ability to suppress both ITD and TKD mutations may be more powerful. Crenolanib has been demonstrated as a potent inhibitor targeting D835 point mutations both in vitro and in vivo with an ongoing Phase II clinical trial [136] . Interestingly, the study of Zirm et al. revealed that ponatinib, a multikinase inhibitor, effectively induced apoptosis of not only the parental FLT3-ITD cell line but also the murine myeloid cells stably transfected with FLT3-TKD N676D, F691I and G697R mutations [139] , which provided a clue to figure out more candidates against FLT3-ITD and TKD mutations by high-throughput screening. Other strategies to explore efficacious inhibitors focus on targeting FLT3-dependent pathways. For instance, CCT137690, a dual FLT3-Aurora inhibitor, successfully inhibited the growth of FLT3-ITD-D835Y cells that were resistant to AC220 and sorafenib [140] . ●●JAK inhibitors

Due to the discovery of activating mutations in JAK2 and dysregulation of JAK-STAT pathway in hematological malignancies, development of

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JAK inhibitors has been promoted. There are several JAK inhibitors in different stages of clinical trials. Among these inhibitors, ruxolitinib, which was demonstrated to have effects on suppressing hematopoiesis, decreasing inflammatory cytokine levels and relieving splenomegaly, has been approved by the US FDA for treatment of splenomegaly in patients with intermediateand high-risk MPN-associated myelofibrosis (staging system unspecified), and by the EMA for treatment of splenomegaly and/or symptoms in patients with MPN-associated myelofibrosis for all disease stages [141] . However, there were no significant effect on improvement of hematologic parameters or reducing burden of JAK2V617F allele. The predominant effect of ruxolitinib in myelofibrosis was not specific for the neoplastic clones [142] . Studies have reported better survival in patients with MPN-associated myelofibrosis treated with ruxolitinib compared with the best available therapy [143] . Other inhibitors including SAR302503, CYT387, lestaurtinib and pacritinib are also in study. However, the benefits of therapy with JAK inhibitors in MPN are moderate due to the fact that the effects of JAK inhibitors are unrelated to mutation status. The combination with various targeting agents for intervention of multiple levels of the signaling pathway may offer better outcomes. Future studies are needed to better understand the role of JAK mutations and associated downstream signal pathways in order to figure out more effective therapy for further clinical benefits.

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Mutations in tyrosine kinase & tyrosine phosphatase  ●●PTP inhibitors

However, the developing inhibitors of PTPs seem to get frozen up. Although numerous compounds including natural products, small molecules and silencing RNAs are under development [144] , efforts are still needed to relate these compounds to clinical application. Among the drugs currently used that have been reported with PTP inhibitory activity, sodium stibogluconate, which was reported able to inhibit SHP-1, SHP-2 and augment antitumor actions of IFN-α2b [145] , combined with other anticancer agents, has been explored in clinical trials of solid tumors [146,147] . Despite that PTPs have been revealed as putative oncogenes or tumor suppressor genes, the inhibitors of PTPs applied in the treatment of cancer are rarely reported. The less understood mechanisms of PTPs in neoplasia may be one of the reasons, with the problem of effective drug development as another. Excitingly, a novel potent and selective TC-PTP (also known as PTPN2) inhibitor has been developed, which has proposed a new approach for potent, highly selective and cell permeable PTP inhibitory

Review

agents [148] . Since the substrates and downstream regulatory mechanisms have not yet been clarified thoroughly, the inhibitors of PTPs are still far away from clinical therapy. However, one thing we can confirm is that there must be a great potential and clinical application prospect waiting for exploration, which may be a similar situation as the initial study of TKIs. Conclusion & future perspective As mentioned above, both PTKs and PTPs play pivotal roles in regulation of signal pathways, which partly decide cellular fate. Due to the important status in cellular functions, the genetic alterations of PTKs or PTPs are among the reasons of carcinogenesis. As the detecting techniques evolve, the majority have been reported nowadays. We present the alterations relevant to hematologic malignancies including mutation, overexpression, deletion, rearrangement and methylation that have been covered. The types of mutation, relevance to clinical diseases and impact on prognosis have been discussed detailedly. We have also discussed the potential therapeutic targets of PTKs and PTPs.

Table 5. The clinical trials of FLT3 inhibitors. Study (year)

Inhibitor

Phase

Dose

Drug combination

Total patients

ITD

TKD mutation

Outcome

Ref.

DeAngelo et al. Tandutinib (2006) Ravandi et al. Sorafenib (2013) Inaba et al.   (2011)

I

150–700 mg twice daily 400 mg twice daily

None

40

8

1

[127]

5-azacytidine

43

40

0

12

5

0

Fiedler et al.(2005)

Sunitinib

I

15

2

2

CRi: 25%; PR: 75%

[130]

Stone et al. (2012)

Midostaurin

Ib

40

9

4

CR: 80%

[131]

Fischer et al. (2010)

 

IIb

Clofarabine and cytarabine 50–75 mg daily, days None 1–28; 80 mg twice daily, days 29–58 50 mg twice daily Daunorubicin and cytarabine 50 or 100 mg twice None daily

Antileukemic effect: 2 of 8 CRi: 27%, CR: 16%, PR: 3% CRi: 17%, CR: 50% PR: 8%

26

9

HI: 39%, PR: 1%, BR: 53%

[132]

Knapper et al. (2006) Pratz et al. (2009) Cortes et al. (2013)  Galanis et al. (2014) 

Lestaurtinib

II

2

3

BR: 30%

[133]

KW-2449

I

Quizartinib Crenolanib

II I

200 mg, 150 mg twice daily

[128] [129]

None None

11

11

0

BR: 45%

[134]

I

60–80 mg twice daily 25–500 mg twice daily 12–450 mg daily

92 (including MDS) 27

None

76

17

0

CR (of any type): 13%, PR: 17%

[135]

II

100 mg every 8 h

None

Not available yet

[136]

BR: Blast response; CR: Complete remission; CRi: CR with incomplete hematological recovery; HI: Hematological improvement; ITD: Internal tandem duplication; MDS: Myelodysplastic syndrome; PR: Partial remission; TKD: Tyrosine kinase domain.

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Review  Zhu, Xiao, Wang, Fu, Zhao & Huang The inhibitors of BCR-ABL1 and FLT3 have been employed clinically for years with inspiring prospects. As expected, the appearance of resistance has limited the scope of application, however, has prompted the evolution of novel targeted drugs. Despite that both BCR-ABL1 and FLT3 inhibitors have shown bright prospects although resistance still exists, the majority of potential therapeutic targets have not been explored yet. Experts have made efforts on clarifying the pivotal roles of different PTKs or PTPs. Much of the information has been uncovered on their oncogenic properties, which could confirm their potential as targets in clinical practice. Although the benefits of inhibiting oncogenic enzymes have been mainly discussed, efforts are encouraged to make on exploring particular drugs owning the ability to activate those enzymes that have putative tumor suppressor functions. There are still unknown mutations or other alterations unexplored. With several decades of research, the remaining challenge refers to the biological roles of PTKs and PTPs in positive or inhibitory functions during the development of neoplasms. Identifying the biological context and signal network of PTKs and PTPs is

essential for future directions, as well as uncovering the disease-related mutations, identifying their substrates and characterizing other pharmacologically relevant pathways. The distance of biological research to clinical application is shortening by the identification of regulatory mechanisms and their potential relevance to cancer. Certainly, exciting new generation of drugs will finally enrich the antitumor therapies. Financial & competing interests disclosure This work was funded in part by the Key Project of the National Natural Science Foundation of China (81230014), the National High Technology Research and Development Program of China (2012AA020905), the National Natural Science Foundation of China (81100387, 81170501), the Major Technology Program (Key Social Development) of the Science Technology Department of Zhejiang Province (2012C13021-1) and the Major Social Development Program of Science Technology Department of Jinhua(2011-3-004). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

EXECUTIVE SUMMARY Protein tyrosine kinases & protein tyrosine phosphatases ●●

Protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs) are both important regulators of signal

transduction in eukaryotic cells. Dysregulation of protein tyrosine phosphorylation caused by genetic alterations of PTKs or PTPs has been revealed to be involved in the pathological process of cancer. Genetic alterations in PTKs in hematologic malignancies ●●

PTKs include receptor tyrosine kinases and nonreceptor tyrosine kinases. Genetic alterations of PTKs have been reported to be associated with hematopoietic malignancies and be valuable in predicting the prognosis.

Genetic alterations in PTPs in hematologic malignancies ●●

Genetic alterations of PTPs that are relevant to hematopoietic neoplasms are all in Class I family, including receptor PTPs, nonreceptor PTPs and the dual-specific protein phosphatases.

Novel therapeutic targets to PTKs & PTPs in hematologic malignancies ●●

Tyrosine kinase inhibitors, such as BCR-ABL1 inhibitors and FLT3 inhibitors, have been applied in treatment of

hematologic malignancies and have shown promising efficacy. However, the inhibitors of PTPs applied in the treatment of cancer are rarely reported. Conclusion & future perspective ●●

The mutations of PTKs and PTPs related to hematologic malignancies have impacts on the carcinogenesis and prognosis. Novel targeted drugs to PTKs and PTPs are promising therapeutic strategies.

●●

Identifying the biological signal network of PTKs and PTPs, uncovering the disease-related mutations and

characterizing other pharmacologically relevant pathways are the remaining challenges, which will provide clues to exploration of target therapies.

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Review

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Proposed a new approach for potent, highly selective and cell permeable PTP inhibitory agents.

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