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Novel Approaches to Target Mutant FLT3 Leukaemia

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Novel Approaches to Target Mutant FLT3 Leukaemia cancers Review Novel Approaches to Target Mutant FLT3 Leukaemia Jörg P. Müller 1,* and Dirk Schmidt-Arras 2 1 Institute of Molecular Cell Biology, Center for Molecular Biomedicine (CMB), Jena University Hospital, 07745 Jena, Germany 2 Institute of Biochemistry, Christian-Albrechts-University Kiel, 24118 Kiel, Germany; [email protected] * Correspondence: [email protected]; Tel.: +49-3641-939-5634 Received: 1 September 2020; Accepted: 25 September 2020; Published: 29 September 2020 Simple Summary: Acute myeloid leukemia (AML) is a haematologic disease in which oncogenic mutations in the receptor tyrosine kinase FLT3 frequently lead to leukaemic development. Potent treatment of AML patients is still hampered by inefficient targeting of leukemic stem cells expressing constitutive active FLT3 mutants. This review summarizes the current knowledge about the regulation of FLT3 activity at cellular level and discusses therapeutical options to affect the tumor cells and the microenvironment to impair the haematological aberrations. Abstract: Fms-like tyrosine kinase 3 (FLT3) is a member of the class III receptor tyrosine kinases (RTK) and is involved in cell survival, proliferation, and differentiation of haematopoietic progenitors of lymphoid and myeloid lineages. Oncogenic mutations in the FLT3 gene resulting in constitutively active FLT3 variants are frequently found in acute myeloid leukaemia (AML) patients and correlate with patient’s poor survival. Targeting FLT3 mutant leukaemic stem cells (LSC) is a key to efficient treatment of patients with relapsed/refractory AML. It is therefore essential to understand how LSC escape current therapies in order to develop novel therapeutic strategies. Here, we summarize the current knowledge on mechanisms of FLT3 activity regulation and its cellular consequences. Furthermore, we discuss how aberrant FLT3 signalling cooperates with other oncogenic lesions and the microenvironment to drive haematopoietic malignancies and how this can be harnessed for therapeutical purposes. Keywords: acute myeloid leukaemia (AML); FMS-like tyrosine kinase 3 (FLT3); oncogenic signaling; re-sistance development; cancer cell vulnerability; haematopoietic niche 1. Introduction Fms-like tyrosine kinase 3 (FLT3) is a member of the PDGFR (class III) receptor-tyrosine kinase (RTK) family and is expressed in human CD34+ haematopoietic stem cells (HSC), lymphoid progenitors, and progenitors cells of the granulocyte/macrophage lineage, including the common myeloid progenitor and the granulocyte/macrophage progenitors. As such, FLT3 participates in the maintenance of pluripotent HSC and contributes to proliferation and differentiation of B-cell progenitors, myelomonocytic and dendritic cells [1–3]. 1.1. Classes of Activating FLT3 Mutations Overexpression of wild type (WT) or oncogenic forms of FLT3 have been implicated in several haematopoietic malignancies [4,5] and inflammatory disorders [6]. Mutations in the FLT3 gene are present in approximately 30% of newly diagnosed AML [7]. Internal tandem duplication (ITD) mutations and tyrosine kinase domain (TKD) mutations are the most common classes of FLT3 abberations in AML. The overall incidence is approximately 23% for FLT3 ITD mutations and 7% for FLT3 TKD Cancers 2020, 12, 2806; doi:10.3390/cancers12102806 www.mdpi.com/journal/cancers Cancers 2020, 12, 2806 2 of 19 Cancers 2020, 12, x 2 of 19 mutations [8]. The majority of ITD mutations occurs in the juxtamembrane region of FLT3, where it disruptsFLT3 TKD its mutations autoinhibitory [8]. The function majority (Figure of ITD1). mu ITDtations mutations occurs canin the also juxtamembrane be located in region the first of kinaseFLT3, domainwhere it [8 disrupts]. The ITD its insertionautoinhibitory site, which function can ( varyFigure in sequence1). ITD mutations and length can is also associated be located with in resistance the first tokinase chemotherapy domain [8] and. The inferior ITD insertion outcome. site, Its which integration can vary site in in sequence the kinase and domain length was is associated identified with as an unfavorableresistance to prognostic chemotherapy factor forand achievement inferior outcome. of a complete Its integration remission, site relapse-free in the kinase survival, domain and overall was survivalidentified of AMLas an unfavorable patients [9]. prognostic factor for achievement of a complete remission, relapse-free survival, and overall survival of AML patients [9]. FigureFigure 1. 1.Activating Activating ITDITD inin thethe juxtamembranejuxtamembrane domain and point mutations mutations in in the the tyrosine tyrosine kinase kinase domaindomain (TKD) (TKD) of of FLT3. FLT3. (a) Inactive,(a) Inactive, autoinhibited autoinhibited conformation conformation of FLT3 of (1RJB.pdb). FLT3 (1RJB.pdb). Residues Residues involved ininvolved ATP-binding in ATP and-binding catalysis and (K644, catalysis D829) (K644, and residuesD829) and subjected residues to subjected mutation into leukemiamutation arein leukemia indicated. (bare) Model indicated. of active (b) Model FLT3 of kinase active domain FLT3 kinase demonstrating domain demonstrating the region for the ITD region insertions for ITD and insertions known frequentand known TKD frequent point mutations TKD point resulting mutations in activationresulting in of activation FLT3. Homology of FLT3. modellingHomology of modelling FLT3 kinase of domainFLT3 kinase was based domain the activewas based conformation the active of theconformation CSF-1 receptor of the (3LCD.pdb) CSF-1 receptor using MODELLER(3LCD.pdb) withinusing theMODELLER UCSF Chimera within 1.14 the software UCSF Chimera package. 1.14 The software activation package. segment The of activation the kinase segment domain of is the marked kinase in pink,domain the juxtamembraneis marked in pink, domain the isjuxtamembrane marked in blue. domain N676K is [ 10marked,11], ITD in reviewedblue. N676K in [9 ].[10,11] References:, ITD D835Yreviewed [12 –in15 [9]], D835H. References: [12–14 D835Y], D835E [12– [1315],14, D835H], D835N [12 [–1314]],, D835VD835E [13,14] [13], I836, D835N del.[ 13[13],16, D835V], I836T [13] [13,], S840GI836 del. [17 ],[13,16] S840insGS, I836T [17 [13]], Y842C, S840G [18 [17],19],, S840insGS Y572C [19 ,20[17]],, N841I Y842C [21 [18,19]], N841K, Y572C [19,22 [19,20]]. , N841I [21], N841K [19,22]. TKD mutations are predominantly found in the activation segment of the kinase domain and stabiliseTKD an activemutations conformation are predominantly of the activation found segmentin the activation (Figure1). segmen TKD mutationst of the kinase are most domain frequently and observedstabilise atan D835active and conformation I836 with theof substitutionthe activation D835Y segment being (Figure the most 1). TKD frequently mutations occurring are most TKD mutation.frequently However,observed otherat D835 substitutions and I836 withinwith the the substitution activation segmentD835Y being were the also most reported. frequently These substitutionsoccurring TKD stabilise mutation. an “open”, However, active other conformation substitutions in which within the the activation activation segment segment is flippedwere also out (Figurereported.1b), These enabling substitutions access of ATP stabilise to the an aspartate “open”, residue active atconformation position 829 in that which serves the as aactivation catalytic basesegment [23]. is Importantly, flipped out FLT3(Figure TKD 1b), mutations enabling access display of diATPfferential to the aspartate sensitivity residue towards at position TKI [24]. 829 that servesUpon as TKIa catalytic treatment, base secondary [23]. Importantly, mutations FLT3 can occur,TKD mutations conferring display TKI-resistance differential viaalteration sensitivity of thetowards ATP/inhibitor-binding TKI [24]. pocket. Additionally, these secondary mutations can, on their own, confer ligand-independentUpon TKI treatment, kinase secondary activation. mutations This has beencan occur, in particular conferring shown TKI- forresistance the N676K via alteration substitution of the ATP/inhibitor-binding pocket. Additionally, these secondary mutations can, on their own, confer Cancers 2020, 12, 2806 3 of 19 (Figure1), which was first identified as TKI resistance-conferring mutation [ 12] and later established as an oncogenic driver mutation [25,26]. 1.2. Biogenesis, Signalling and Regulation of the FLT3 Receptor Tyrosine Kinase The FLT3 protein is co-translationally translocated into the endoplasmic reticulum (ER). Here, the luminal-faced N-terminus of the receptor undergoes multistep glycosylation and folding, as mediated by the ER luminal enzyme machinery [1]. The ER quality control system ensures that only properly folded FLT3 molecules egress the ER, get further glycosylated at the Golgi system to finally traffic to the plasma membrane (Figure2a) [27,28]. There is an increasing body of evidence that activating mutations in receptor tyrosine kinases (RTK) cause aberrant intracellular localisation of these proteins. The reader is referred to a recent review [27]; which summarises molecular mechanisms and consequences of RTK mislocalization. Activating mutations in FLT3 were also shown to result in prolonged association of mutant FLT3 within the ER quality control and, therefore, resulting in a predominant ER localisation of FLT3 [28]. Aberrant activation of FLT3 at endomembranes results in altered downstream signalling quality [29,30]. In particular, the ER-resident pool of mutant FLT3 is responsible for phosphorylation and activation
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