Abstract
The identification of recurrent driver mutations in genes encoding tyrosine kinases has resulted in the development of molecularly-targeted treatment strategies designed to improve outcomes for patients diagnosed with acute myeloid leukemia (AML). The receptor tyrosine kinase FLT3 is the most commonly mutated gene in AML, with internal tandem duplications within the juxtamembrane domain (FLT3-ITD) or missense mutations in the tyrosine kinase domain (FLT3-TKD) present in 30–35% of AML patients at diagnosis. An established driver mutation and marker of poor prognosis, the FLT3 tyrosine kinase has emerged as an attractive therapeutic target, and thus, encouraged the development of FLT3 tyrosine kinase inhibitors (TKIs). However, the therapeutic benefit of FLT3 inhibition, particularly as a monotherapy, frequently results in the development of treatment resistance and disease relapse. Commonly, FLT3 inhibitor resistance occurs by the emergence of secondary lesions in the FLT3 gene, particularly in the second tyrosine kinase domain (TKD) at residue Asp835 (D835) to form a ‘dual mutation’ (ITD-D835). Individual FLT3-ITD and FLT3-TKD mutations influence independent signaling cascades; however, little is known about which divergent signaling pathways are controlled by each of the FLT3 specific mutations, particularly in the context of patients harboring dual ITD-D835 mutations. This review provides a comprehensive analysis of the known discrete and cooperative signaling pathways deregulated by each of the FLT3 specific mutations, as well as the therapeutic approaches that hold the most promise of more durable and personalized therapeutic approaches to improve treatments of FLT3 mutant AML.
Highlights
Acute myeloid leukemia (AML) is characterized by the malignant transformation of a hematopoietic stem/progenitor cell (HSC)
The presence of FMS-like tyrosine kinase 3 (FLT3)-ITD in leukemic stem cells (LSCs) is associated with expression of CD123 [128,129], encoding the IL3 receptor subunit alpha (IL-3RA) which is overexpressed in 45% of AML patients
The identification of models to study LSCs harboring FLT3-ITD mutations or complex cytogenetics will offer the best hope of characterizing the oncogenic signaling that may afford LSC specific targeting in high-risk or poor prognosis AML patients
Summary
Acute myeloid leukemia (AML) is characterized by the malignant transformation of a hematopoietic stem/progenitor cell (HSC). Advances in genomic sequencing techniques and technologies have identified recurrent mutations which have begun to help elucidate the complex genomic landscapes underpinning the disease, both at diagnosis and following relapse [7,8] These studies have begun to associate individual mutations, and combinations of mutations, with overall survival (OS) [9]. Whole genome sequencing analysis has revealed that mutations are common in signaling genes that encode for the tyrosine kinases, FLT3, JAK2, cKIT, for phosphatases, PTPN11, PTPRT, PTPN14, and for Ras GTPases, KRAS and NRAS, and represent 59% of all gene mutations [8,9] These are often independently associated with poor outcomes [10]. IInnddeeeedd,, iinn 22001177,, tthhee FDDAA apprrovveedd thee FLT3 inhibitor midostaurin inincocmombibniantaiotinown itwhisthtansdtaanrdaorfdcaoref cchaerme octhheemraoptyheforarpthye ftorerattmheenttreoaftnmewenlty-odfiagnnewosleyddFLiaTg3n-omsuedtanFtLAT3M-mLuptaatnietnAtsM[3L6]p,astuiepnetrsse[3d6in],gsaunpeerrsaeodfinvgeraynliettrlae oafdvearnycelmittelentaidnvAanMceLmthenertaipnyA[3M7L]. theraDpyes[p3i7t]e. the recurrence of FLT3-activating mutations in AML, the differences in oncogenic pathwDaeysps iitne ptahteienretscuhrarrebnocreinogfeFitLhTer3-IaTcDtivoartTinKgDmmuutatatitoionnss isntilAl rMeqLu,irtehceladriffifcearetinocne.sTihne soingcnoifigecannict padatvhawncaeyms iennptsatriecnetns thlyarmboardinegienituhnebr iIaTsDedo,rqTuKaDntmitauttiavteiopnhsosstipllhroepqruoitreeocmlaircifipcraotfiiolnin. gTh[3e8s–ig4n1]ifihcaavnet athdevapnocetemnetinatls rteocepnrtolyvimdeaduesinwunitbhiaasedfu, qlluanntnitoattaivtieonphofspthhoeprsoitgenoaml icpaptrhowfilainygs [d38e–re4g1u] hlaatveedthine preostpeonntisael to ipnrdoivviiddeuaulsmwuithatiaonfus,lloarnfnoolltoawtioinngoafcqthueirseidgnraesl ipstaatnhcweaiynsdudceeredgbuyla‘tdeduailnlerseisopnosn’ s(e.gto., iFnLdTi3v-iIdTuDa-lTmKuDt)at[i4o2n]s. , Horerfeoilnlo, wwiengreavcieqwuirtehde rkensoiswtanncoencinodguenceicdsbigyn‘adliunagl pleastihownsa’y(se.mg.,odFuLTla3t-eIdTDinTFLKTD3)m[4u2t]a. nHteAreMinL, ,waendretvhiewrotlehsetkhnaot weanchonocfotghendiciffseigrennatliFnLgTp3amthuwtatyisonmsopdluaylaitnedthien eFmLTer3gmenucteanotf AtaMrgLet,eadn-dthethraepryolreessitshtatnceeacfholloofwthinegdtihffeeruesnet oFfLfiTr3stmanudtatsieocnosnpdlagyenienrathtieonemTKerIgse. nAcefuonf dtarmgetnetda-l tuhnedraeprsytanredsiinsgtanofcethefoullnoiwqiuneganthdereudsuendoafntfisrisgtnanlidng speactohnwdaygsenaessraotciioantedTKwIist.h eAachfuinnddaimviednutaall, uorndeurasltamnudtiantgioonfs,thheoludnsipquroemainsde froerdtuhneddaenvtesliogpnmaleinngt opfaltohnwga-lyasstainssgotchiaetreadpewuittihc eaapcphroinacdhivesidtuoatlr,eoart dthueaslempouotartpiornosg,nhooslids sApMroLmpiasteiefnotrs.the development of long-lasting therapeutic approaches to treat these poor prognosis AML patients
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