Kapur, Reuben

Pandey, Ruchi

Haematologica

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Ruchi Pandey

Reuben Kapur

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Editorials2330 haematologica | 2019; 104(12)DNA damage on the DOCK in FLT3-ITD-driven acute myeloid leukemiaRuchi Pandey and Reuben KapurHerman B Wells Center for Pediatric Research, Indiana University School of Medicine, IN, USAE-mail: RUCHI PANDEY -  pandeyru@iupui.edu  or REUBEN KAPUR - rkapur@iupui.edudoi:10.3324/haematol.2019.231340Induction of DNA damage by chemotherapeutics hasbeen the mainstay of cancer therapy irrespective ofthe origin of the cancer. However, in acute myeloidleukemia (AML) responses to intensive chemotherapydiffer greatly, with the success rate ranging very widelyfrom 94% to 17% depending upon the karyotype of thepatients.1 In particular, AML patients with normal cytoge-netics initially respond to DNA damaging agents but fre-quently relapse and have a 5-year survival rate of around30%. The inferior survival in these patients correlateswith the presence of internal tandem duplications (ITD)in FLT3, a cytokine receptor with tyrosine kinase activity,found in almost one-third of AML patients.Constitutively active FLT3-ITD contributes to increasedproliferation and survival of myeloid progenitor cells.Although FLT3-ITD by itself is not considered a driver ofAML, the presence of the mutation at both diagnosis andrelapse highlights the importance of FLT3-ITD in resist-ance of leukemia-initiating cells to therapy. FLT3-ITD canactivate all the major signaling pathways, such asRas/ERK, JAK/STAT5 and PI3K/AKT but we still do notcompletely understand how these lead to resistance tochemotherapy and whether they create any vulnerabili-ties that could be exploited. FLT3-ITD activates theNADPH oxidase system through RAC1 to augment theproduction of reactive oxygen species (ROS) and a conse-quent adaptive response involving RAD51-mediatederror prone repair and enhanced genomic instability.2Interestingly, increased ROS production is not associatedwith the tyrosine kinase domain mutated FLT3, whichincidentally is also not associated with poor prognosis.These suggest that increased DNA damage response(DDR) and genomic instability are important for the poorresponse to therapy in FLT3-ITD-positive (FLT3-ITD+)AML patients. In the current issue of Haematologica, Wu etal.3 provide evidence of involvement of a FLT3-ITD/DOCK2/ RAC1 self-sustaining positive feedbackloop leading to upregulation of DDR proteins that con-tributes to chemotherapy resistance (Figure 1). They pro-vide evidence for the crucial role played by DOCK2 inmediating chemoresistance through regulating theRAC1/STAT5/DDR axis.3 Although expression of FLT3-ITD has been associated with resistance to chemothera-py and it has long been known that inhibition of signalingby kinase inhibitors can sensitize leukemic cells,4 this hadnot been extensively explored or utilized in the clinic.Only recently, is it becoming evident that midostaurin(PKC412), a multi-kinase inhibitor, is much more effec-tive at inducing sustained remissions when used in com-bination with chemotherapy than when used as single-agent therapy.5 The results presented by Wu et al.3 furtheremphasize the role of chemo-sensitization through inhi-bition of signaling by mutant FLT3 and provide a way for-ward for improving the clinical outcome in FLT3-ITD+AML patients. Activation of RAC1 by FLT3-ITD has been recognizedas the major contributor to enhanced DDR but the ubiq-uitous expression of RAC1 and its involvement in multi-ple processes makes targeting RAC1 specifically inleukemic cells a challenge.6 DOCK2, an atypical guaninenucleotide exchange factor, has previously been identi-fied as an intermediate between FLT3-ITD and STAT5.7DOCK2 has much more restricted expression, actsupstream of RAC1 and is required for upregulation of theDDR pathway. Combining loss of DOCK2 with cytara-bine produced a similar increase in cytotoxicity as thatobserved with inhibiting the kinase function of FLT3-ITD(Figure 1).3 The alternative pathways from FLT3-ITD,such as FAK/TIAM1 and DOCK2, culminating in activa-tion of RAC1 and subsequent nuclear translocation ofSTAT5 provide additional points of vulnerability thatcould be therapeutically exploited to overcome acquireddrug resistance in response to FLT3-specific small mole-cule inhibitors.7,8 DOCK2 mutations leading to activationof RAC1 have also been identified in gastrointestinal andprostate cancers. It remains to be seen if similar deregula-tion of the DDR pathway is involved in carcinogenesisacross different types of cancers.The synthetic lethality observed with DOCK2 inhibi-tion upon treatment with cytarabine could be attributedto downregulation of FLT3-ITD and the DDR pathway.3However, Wu et al.3 did not observe a similar synergismwhen inhibitors of individual components of the DDRsuch as CHK1 (MK8776) or WEE1 (MK1775) were usedin combination with cytarabine. As expected, the concur-rent use of inhibitors of CHK1 and WEE1 with DOCK2inhibition showed marginal improvements since DOCK2knockdown significantly reduces both FLT3-ITD andthese DDR pathway proteins.3 Functional redundancybetween DDR proteins may account for lack of syner-gism between MK8776 or MK1775 and cytarabine.3Although targeting DOCK2 appears to be more benefi-cial; the clinical translation of co-targeting DOCK2 is lim-ited due to non-availability of potent and specificinhibitors. Currently two small molecule inhibitors ofDOCK2 are available: the chemically synthesized 4-[3’-(2’’-chlorophenyl)-2’-propen-1’-ylidene]-1-phenyl-3,5-pyrazolidinedione (CPYPP)9 and a naturally occurringcholesterol sulfate.10 The effects of these inhibitors ofDOCK2 have been evaluated in the immune system andthey have been found to block RAC1 activation but acomprehensive evaluation in AML models has not beencarried out. The significance of targeting DOCK2 in sen-sitizing FLT3-ITD+ AML cells to chemotherapy demon-strated by Wu et al.3 may provide the impetus for devel-opment of therapeutic strategies to target DOCK2 incombination with standard chemotherapy leading to bet-ter prognosis for these AML patients.   While the study by Wu et al.3 focuses only on FLT3-ITD+ AML, similar defects in the DDR are known to beassociated with several other AML driver mutations,specifically the epigenetic regulators. Genes such asDNMT3A and TET2, which are very frequently mutatednot only in the leukemic cells but also in the pre-leukemic clones, are known to regulate the DDR.11,12Cells carrying mutations in these genes are known tohave an increased propensity to accumulate DNA dam-age. Interestingly, they are also found in non-randomassociation with FLT3-ITD and their concurrent occur-rence is sufficient for AML initiation. Similar to FLT3-ITD these pre-leukemic mutant clones tend to be chemo-resistant and they expand following elimination ofleukemic cells by chemotherapy. The pre-leukemicclones are believed to evolve into leukemic cells due toinherent genomic instability and acquisition of addition-al mutations. The clinical relevance of alterations in theDDR in AML due to genetic mutations is underscored bythe increase in survival with induction therapy doseescalation observed in patients carrying mutantDNMT3A but not in their wildtype counterparts.13 Withbetter understanding of the driver mutations in AML andtheir role in normal cell functions, it is becoming appar-ent that an altered DDR is a common underlying themein AML and pre-leukemic mutant cells. The research byWu et al.3 emphasizes that combinatorial treatmentstrategies tailored to the specific driver mutation-depen-dent vulnerability in the DDR need to be explored fur-ther. A similar approach of inducing synthetic lethalityby using PARP inhibitors in combination with standardchemotherapy in BRCA mutated gynecological cancershas led to improved patients’ outcomes in the clinic.14Interestingly, FLT3-ITD+ leukemic cells can be sensitizedto PARP inhibitors when used in combination withAC220, a second-generation FLT3 inhibitor, leading toenhanced survival.15 It is to be hoped that these studieswill spur development of rational combinations ofinhibitors of FLT3 signaling with DDR inhibitors leadingto a broader range of options to improve patients’ out-comes and survival. AcknowledgmentsRP is supported by an award from the Ralph W. and GraceM. Showalter Research Trust and Indiana University School ofMedicine. RK is supported by research grants from NIH-R01CA173852, R01CA134777, R01HL146137, andR01HL140961 and the Riley Children’s Foundation. The con-tent of this editorial is solely the responsibility of the authors anddoes not represent the views of the funding agencies. Editorialshaematologica | 2019; 104(12) 2331Figure 1. FLT3-ITD and DOCK2 maintain the bal-ance between the DNA damage response andchemosensitivity. The positive signaling feedbackbetween FLT3-ITD and DOCK2 upregulates the DNAdamage response (DDR) through RAC1 leading to adecrease in chemosensitivity (CS) of acute myeloidleukemia (AML) cells. The balance can be tilted infavor of chemotherapy by downregulation of DOCK2or inhibition of FLT3-ITD or DDR proteins which sen-sitizes the AML cells.References1. Byrd JC, Mrozek K, Dodge RK, et al. Cancer, Leukemia Group B.Pretreatment cytogenetic abnormalities are predictive of inductionsuccess, cumulative incidence of relapse, and overall survival in adultpatients with de novo acute myeloid leukemia: results from Cancerand Leukemia Group B (CALGB 8461). Blood. 2002;100(13):4325-4336. 2. Sallmyr A, Fan J, Datta K, et al. Internal tandem duplication of FLT3(FLT3/ITD) induces increased ROS production, DNA damage, andmisrepair: implications for poor prognosis in AML. Blood.2008;111(6):3173-3182. 3. Wu M, Li L, Hamaker M, Small D, Duffield AS. FLT3-ITD cooperateswith Rac1 to modulate the sensitivity of leukemic cells to chemother-apeutic agents via regulation of DNA repair pathways.Haematologica. 2019;104(12):2418-2428. 4. Seedhouse CH, Hunter HM, Lloyd-Lewis B, et al. DNA repair con-tributes to the drug-resistant phenotype of primary acute myeloidleukaemia cells with FLT3 internal tandem duplications and isreversed by the FLT3 inhibitor PKC412. Leukemia. 2006;20(12):2130-2136. 5. Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin pluschemotherapy for acute myeloid leukemia with a FLT3 mutation. NEngl J Med. 2017;377(5):454-464. 6. Marei H, Malliri A. Rac1 in human diseases: the therapeutic poten-tial of targeting Rac1 signaling regulatory mechanisms. SmallGTPases. 2017;8(3):139-163. 7. Wu M, Hamaker M, Li L, Small D, Duffield AS. DOCK2 interactswith FLT3 and modulates the survival of FLT3-expressing leukemiacells. Leukemia. 2017;31(3):688-696. 8. Chatterjee A, Ghosh J, Ramdas B, et al. Regulation of Stat5 by FAKand PAK1 in oncogenic FLT3- and KIT-driven leukemogenesis. CellRep. 2014;9(4):1333-1348. 9. Nishikimi A, Uruno T, Duan X, et al. Blockade of inflammatoryresponses by a small-molecule inhibitor of the Rac activatorDOCK2. Chem Biol. 2012;19(4):488-97. 10. Sakurai T, Uruno T, Sugiura Y, et al. Cholesterol sulfate is a DOCK2inhibitor that mediates tissue-specific immune evasion in the eye.Sci Signal. 2018;11(541)pii:eaao4874.11. Guryanova OA, Shank K, Spitzer B, et al. DNMT3A mutations pro-mote anthracycline resistance in acute myeloid leukemia viaimpaired nucleosome remodeling. Nat Med. 2016;22(12):1488-1495. 12. Pan F, Wingo TS, Zhao Z, et al. Tet2 loss leads to hypermutagenicityin haematopoietic stem/progenitor cells. Nat Commun.2017;8:15102. 13. Sehgal AR, Gimotty PA, Zhao J, et al. DNMT3A mutational statusaffects the results of dose-escalated induction therapy in acute myel-ogenous leukemia. Clin Cancer Res. 2015;21(7):1614-1620. 14. Lord CJ, Ashworth A. PARP inhibitors: synthetic lethality in the clin-ic. Science. 2017;355(6330):1152-1158.15. Maifrede S, Nieborowska-Skorska M, Sullivan-Reed K, et al.Tyrosine kinase inhibitor–induced defects in DNA repair sensitizeFLT3(ITD)-positive leukemia cells to PARP1 inhibitors. Blood.2018;132(1):67-77Editorials2332 haematologica | 2019; 104(12)Pathophysiology and current therapies in chronic lymphocytic leukemiaChronic lymphocytic leukemia (CLL) is the most fre-quent leukemia in western countries. It is characterizedby the accumulation of mature B lymphocytes in theperipheral blood, peripheral lymphoid organs and bonemarrow. CLL displays a heterogeneous clinical course,ranging from protracted indolent disease with no require-ment for treatment in some patients to rapid disease pro-gression and subsequent treatment refractoriness in oth-ers.1-3CLL progression is a reflection of the complex interplaybetween genomic drivers of disease and interactions withthe microenvironment.4 Whole genome/exome profilingby next-generation sequencing has revealed that the clon-al composition of CLL is constantly reshaped during dis-ease progression. It has been proposed that CLL exhibitsa stochastic model of progression with the existence of a‘trunk’ tumor population and numerous ‘branches’ thatcan act as tumor progenitors. According to this model,the subclonal topography of CLL arises over time as aresult of an initial driver mutation which leads to malig-nant transformation and is observed in all tumor cells –the trunk population. This is followed by secondary driv-er mutations in distinct subclones which are selected byintraclonal competition or treatment, and are likely tocontribute to disease progression. Finally, CLL relapse hasbeen attributed to the expansion of highly fit, often treat-ment-selected subclones (branches) carrying mutations inthe DNA damage response (DDR) genes TP53 and ATM,SF3B1 or NRAS.5,6 As a result, a significant proportion ofrelapsed/refractory CLL can be attributed to the function-al loss of the DDR.For several decades, alkylating agents and purineanalogs were the principal therapies for CLL, augmentedby the addition of monoclonal antibodies. The lastdecade has seen an expansion in the number of com-pounds targeting specific aspects of the CLL phenotype,from the interactions of tumor cells with the microenvi-ronment and B-cell receptor signaling to anti-apoptoticcellular pathways, heralding a new era of CLL therapybased on targeted treatment approaches.7-10 In particular,new inhibitors of signaling pathways that are critical toCLL survival and proliferation, such as Bruton tyrosinekinase (BTK), phosphoinositide-3 kinase (PI3K), and theanti-apoptotic protein Bcl-2, have changed the manage-ment of many CLL patients.Despite the array of available therapeutic options, CLLremains, at present, an incurable condition.11 Firstly, theacquisition of DDR gene defects such as TP53 deletionsand/or mutations renders CLL patients refractory to con-ventional chemoimmunotherapies. The clinical responseto the BTK inhibitor, ibrutinib, is encouraging for somebut not all refractory tumors.12 Secondly, clonal selectionFine tuning of p53 functions between normal and leukemic cells: a new strategy for the treatment of chronic lymphocytic leukemiaTatjana StankovicInstitute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UKE-mail: TATJANA STANKOVIC - t.stankovic@bham.ac.ukdoi:10.3324/haematol.2019.230896

DNA Damage On The DOCK In FLT3-ITD-Driven Acute Myeloid Leukemia

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