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Leukemia Research 35 (2011) 27–29

Contents lists available at ScienceDirect

Leukemia Research

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uest editorial

re SRC family kinases responsible for imatinib- and dasatinib-resistant chronicyeloid leukemias?

eywords:hronic myeloid leukemiaRC family kinasematinib

Philadelphia-positive (Ph+) chronic myeloid leukemia (CML) ismyeloproliferative disease caused by the BCR-ABL fusion gene.

he BCR-ABL fusion gene encodes a constitutively activated tyro-ine kinase and is the product of a well-defined translocation eventetween the ABL kinase gene on chromosomes 9 and the BCRene on chromosome 22 [1]. More than 90% CML patients startith a chronic phase, progress to an accelerated phase and even-

ually develop “blast crisis”, which resembles an acute leukemia1]. Ten years ago, allogeneic bone marrow transplantation (BMT)as the recommended treatment for newly diagnosed patientsith CML and was regarded as a ‘curative’ therapy for CML [2].

ts major drawback relates to the age and availabilities of donors3]. A great effort has been put to find a new way to overcome thisimitation. With the success of “targeted” tyrosine kinase inhibitorTKI) therapy in BCR-ABL-driven CML, the BCR-ABL kinase inhibitormatinib mesylate (Gleevec/Glivec, formerly STI571; Novartis) hasecome the first-line therapy for CML. Imatinib competitively bindso the ATP binding site of BCR-ABL, locks it in a closed confor-

ation, and therefore inhibits tyrosine kinase activity [4]. Afteryears of imatinib treatment, the rate of complete cytogentic

esponse among patients has been reported to be 87%, while only% of patients progress to accelerated-phase CML or blast crisis [5].espite this response, imatinib does not cure CML and resistance

o imatinib eventually develops. One major reason for the resis-ance is intractable point mutations in the BCR-ABL kinase domainike T315I [6]. In addition to resistance, it is now understood thatCR-ABL expressing leukemia stem cells (LSCs) are insensitive to

matinib treatment [7,8].Although imatinib can effectively inhibit BCR-ABL kinase activ-

ty and prolong the survival of CML patients, it cannot eradicateSCs and therefore cure the disease. To resolve the resistance ofSCs to kinase inhibitors and fully understand how BCR-ABL sig-als in these LSCs, research has been undertaken to identify uniqueolecular pathways that are dependent on or independent of BCR-

BL kinase activity. Several have been identified to play importantoles in CML development and specifically LSC survival, includ-ng the Wnt/ˇ-catenin, Hedgehog, Alox5, Pten and FoxO pathways9–14] (Fig. 1). These new approaches also provide some potentialargets for curative therapy. Arachidonate 5-lipoxygenase (Alox5)

145-2126/$ – see front matter. Published by Elsevier Ltd.oi:10.1016/j.leukres.2010.07.032

gene is a critical regulator for LSCs in BCR-ABL-induced CML. In theabsence of ALOX5, BCR-ABL failed to induce CML in a mouse modelfor human CML. Similarly, treatment of these CML mice with theALOX5 (5-LO) inhibitor zileuton impaired the function of LSCs andprolonged the survival of treated mice. These results demonstratedthat a specific target gene can be found in LSCs and its inhibitioncan completely disrupt the function of LSCs [11]. A Phase I/II studyto evaluate the safety of zileuton in combination with imatinibin CML patients has been initiated and is now recruiting patients(ClinicalTrials.gov Identifier: NCT01130688).

Besides these unique signal pathways, SRC family kinases (SFKs)have also been shown to be functionally important in CML cells.SFKs are a group of structurally related non-receptor protein tyro-sine kinases, containing four similar SRC homology domains [15].Members of this kinase family include BLK, FGR, FYN, HCK, LYN, LCK,c-SRC, YRK and YES [15]. Among them, HCK and LY N are known tointeract with BCR-ABL [16]. HCK binds directly to BCR-ABL throughSH domains and kinase domain as well as the C-terminal tail,involving kinase-dependent and -independent components. Theinteraction with HCK or other SRC family members is required fortransformation of the myeloid leukemia cell line by BCR- ABL [17].LYN co-immunoprecipitates with BCR-ABL and regulates BCR-ABLfunction through SH2-containing tyrosine phosphotase-1 (SHP-1)[18]. HCK and LYN are activated in CML cells in a manner that isapparently kinase-independent, as it is not inhibited by the BCR-ABL kinase inhibitor imatinib. The function of SRC family kinasesin CML is also supported by the recent findings that SFKs: FGR, LYNand HCK are required for the proliferation of BCR-ABL-expressingpre-B-cells and that these SFKs remain active following imatinibinhibition of BCR-ABL kinase activity in leukemia cells [19,20].

In this issue of Leukemia Research, Hayette et al. presentevidence defining the frequency with which SFKs are involvedin imatinib- and dasatinib-resistant CML patients [21]. Theyidentified a high frequency of SFKs involvement in tyrosinekinase inhibitor-resistant CML and noted in particular elevatedSFKs activities in patients with progressed disease and blastcrisis. In this retrospective study, four categories of imatinib-and dasatinib-treated patients (imatinib resistant/dasatinib-responsive; dasatinib-resistant; blast crisis or CML progression andT315I or F317L mutated patient receiving omacetaxine treatment)were included. Transcript levels of HCK, LYN and another SFK func-

tionally related gene BTK were screened in a large population ofCML patients. Additionally and more importantly, protein expres-sion of SFKs was analyzed in 46 patients (146 total follow-upsamples). SFKs activation was elevated in more than 50% of resis-

28 Guest editorial / Leukemia Research 35 (2011) 27–29

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Fig. 1. Signal pathways dependent or indep

ant CML patients, and this increase more significantly correlatesith disease progression. Interestingly, activation of SFKs expres-

ion is not likely caused by BCR-ABL mutation, as four BCR-ABLutated patients showed concomitant SFKs activation similar to

hat seen in patients expressing a wild-type BCR-ABL.Hayette et al. also followed five patients possessing BCR-ABL

utations who were receiving omacetaxine treatment [21]. Omac-taxine (also known as homoharringtonine) targets leukemic cellshrough a mechanism of action that differs from TKIs [22]. Omac-taxine has shown promising clinical activity in CML patientsesistant to imatinib or other TKIs and is currently in a phase IIIlinic trial in United States [22]. It functions as a protein synthesisnhibitor and can inhibit ABL, HSP90 and MCL-1 protein expres-ion in CML cells [23]. SFKs were also shown to be activated inatients with BCR-ABL mutation under omacetaxine treatment, but

n one patient resistant to omacetaxine treatment, SFKs remainednactivated. The SFKs activation after omacetaxine treatment mayrovide insights into the possible mechanisms by which the drugannot eradicate leukemia cells and also suggests some unknownathways are being activated. These findings indicate that SFKsre potential therapeutic targets of imatinib-, dasatinib- ormacetaxine-resistant CML and also are suggestive of a new strat-gy that may effectively target leukemia cells and thus cure CML.

onflicts of interest

The author stated no conflict of interests.

cknowledgements

No support for this work.

eferences

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[4] Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM, et al. Activity ofa specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronicmyeloid leukemia and acute lymphoblastic leukemia with the Philadelphiachromosome. N Engl J Med 2001;344:1038–42.

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ia Res

Guest editorial / Leukem

Yaoyu Chen ∗

Department of Medicine, University of MassachusettsMedical School, Lazare Research Building 280J,

364 Plantation Street, Worcester,MA 01605, USA

earch 35 (2011) 27–29 29

∗ Tel.: +1 08 856 4157, fax: +1 508 856 6797.E-mail address: yaoyu.chen@umassmed.edu

14 July 2010Available online 19 August 2010