CCR TranslationsCommentary on Saiya-Cork et al. p. 2679

Insulin Receptor Activation in Deletion 11q Chronic Lymphocytic Leukemia

Jennifer R. Brown

The chromosomal abnormalities characteristic of chronic lymphocytic leukemia (CLL) are well studied,

but the mechanisms underlying their contribution to pathogenesis are only partially elucidated. Integrated

genomic profiling, focused on deletion 11q, has identified elevated expression of the insulin receptor in a

subgroup of CLLs and associated it with worse outcomes. Clin Cancer Res; 17(9); 2605–7. �2011 AACR.

In this issue of Clinical Cancer Research, Saiya-Cork andcolleagues used integrative genomic profiling to identifythat the insulin receptor (INSR) is significantly overex-pressed in about 25% of chronic lymphocytic leukemias(CLL), many of which carry deletion 11q (1). Deletion 11qhas been associated with marked lymphadenopathy andrapid disease progression in CLL, leading to short overallsurvival (2, 3). At diagnosis or initiation of first therapy,deletion 11q is the most common high-risk abnormality inCLL. Although the molecular pathogenesis of CLL witheach characteristic chromosome abnormality is beingintensively studied, much remains to be understood. Mostinterest in 11q deletion has focused on loss of the ataxiatelangiectasia mutated (ATM) gene, a well-known tumorsuppressor gene involved in cell cycle checkpoint signalingand DNA repair. Because 11q deletion generally onlyaffects one of the two chromosomes, the other ATM allelewould be expected to be mutated if ATM is a key target forCLL pathogenesis. One report foundmutations in the otherATM allele in 36% of 11q CLLs and found that having sucha mutation was associated with worse survival than 11qdeletion alone (4). Even if reproducible, those findingsimply that two thirds of 11q deletion CLLs do not havemutation of the other ATM allele, suggesting either a genedosage effect or the involvement of other genes in patho-genesis. Providing support for the involvement of othergenes is the observation that families with ataxia telangiec-tasia, due to germline mutation of the ATM gene, do nothave high rates of CLL.Saiya-Cork and colleagues used array-based expression

profiling to identify the INSR as a significantly differentiallyexpressed gene between CLLs with and without deletion of11q and they confirmed this finding with quantitative PCRas well as FACS analysis and Western blotting. They found

that INSR expression varied continuously across a largecohort of CLLs, with about 60% of CLLs showing someINSRmRNA expression, and deletion 11q CLLs enriched inthe highest expressing group. Approximately two thirds ofthe deletion 11q CLLs showed elevated INSR expression.Importantly, deletion 17p CLLs were not enriched in thehighest-expressing groups, suggesting that INSR expressionis not merely a proxy for aggressive or proliferative disease.Saiya-Cork and colleagues were not able to identify acandidate gene or a common pattern of deletion within11q that explains INSR overexpression, although they didnot comment on microRNAs. The importance of micro-RNAs in CLL has become increasingly clear (5, 6), andcertainly, deletion of a microRNA in 11q that could targetthe INSR might lead to its overexpression. However,because only about two thirds of the deletion 11q patientsshowed INSR overexpression, and some patients in theother cytogenetic groups also showed overexpression, themechanism of INSR expression is undoubtedly complex,likely involving either multiple mechanisms, or onemechanism with multiple regulators.

Saiya-Cork and colleagues further showed that theINSR expressed in these CLLs was functional, in thatinsulin is able to induce activation of the AKT andRAS/RAF/extracellular signal regulated kinase (ERK)pathways and tyrosine phosphorylation of IRS1. Thesesignals provide survival support to the CLLs, which showa reduction in apoptosis in response to insulin. In fact,insulin leads to AKT phosphorylation at about the samelevels as stimulation through the B-cell receptor (BCR),which is well known to provide survival signals to CLLcells (7). These findings of activated signaling suggest apossible mechanism of rapid clinical translation, becausedirect potent inhibition of the INSR itself would presum-ably be clinically problematic. Multiple drugs already inthe clinic inhibit phosphatidylinositol 3-kinase (PI3K),which is downstream of the INSR and upstream of AKT,and at least to date, these PI3K inhibitors have not beenreported to cause substantial clinical problems withhyperglycemia (8).

The PI3K inhibitor most tested in hematologic malig-nancies and that has very significant activity in CLL is CAL-101 (9). CAL-101 is a specific inhibitor of the p110d

Authors' Affiliation: Department of Medical Oncology, Dana-FarberCancer Institute, Boston, Massachusetts

Corresponding Author: Jennifer R. Brown, Department of Medical Oncol-ogy, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115.Phone: 617-632-4894; Fax: 617-582-7909;E-mail: Jennifer_Brown@dfci.harvard.edu

doi: 10.1158/1078-0432.CCR-11-0295

�2011 American Association for Cancer Research.

ClinicalCancer

Research

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catalytic subunit of PI3K. The p110d isoform showsrestricted expression in leukocytes and is not thought tobe involved in insulin signaling, which is usually mediatedby the ubiquitously expressed p110a or p110b catalyticsubunits. In CLL, inhibition of the p110d isoform withCAL-101 has been shown to block the signaling effects ofstimulation through the BCR or CD40 (10, 11), but insulinsignaling has not been investigated (Fig. 1). The PI3Kisoform involved in insulin signaling in CLL cells will needto be determined experimentally, because the alpha anddelta isoforms are both expressed. If insulin signaling inCLL cells is mediated by the p110a subunit, as it is in othercell types, then a pan-PI3K or PI3Ka inhibitor would berequired to inhibit insulin signaling and would be expectedto have better clinical activity than CAL-101 in the CLLsubgroup that overexpresses the INSR, albeit at a possiblecost of hyperglycemia not seen with CAL-101. Of course, ifinsulin signaling in CLL is actually mediated by the deltaisoform, then INSR overexpression might be associatedwith very good response to CAL-101. Whether the vari-able sensitivity of different CLLs to PI3K inhibitors isrelated to INSR expression can easily be tested in vitro.Analysis of INSR expression levels in the CLLs of patientsenrolled on clinical trials of these inhibitors is alsosimple. Depending on the results, these data could leadfairly quickly to rational selection of patients for a pro-spective clinical trial.

Finally, Saiya-Cork and colleagues found that increasingexpression of INSR was associated with lymph node dis-

ease, as well as shorter time to first treatment (TTFT) andoverall survival (OS). The association with lymph nodedisease may be related to the known association of lymphnode disease with 11q deletion (3). However, the findingsfor TTFT andOS are true even when CLLs with deletion 11qare excluded, showing that the higher risk associated withINSR overexpression may apply more generally in CLL. Thesize of their study makes it difficult to determine defini-tively whether these effects are truly independent of unmu-tated IGVH and positive ZAP-70, which are enriched in thehigh INSR CLLs. Interestingly, however, the authorsobserved that, in the ZAP-70–negative CLLs, high INSRexpression was predictive of steady progression to treat-ment, similar to that of ZAP-70–positive CLLs. Given thatZAP-70 expression has been associated with higher BCRsignaling in CLL (12), this finding suggests that perhapsactivation of the INSR is substituting for ZAP-70 by activat-ing shared signaling pathways leading to disease progres-sion (Fig. 1). The clinical utility of this finding as aprognostic marker will depend on its reproducibility, theavailability of accurate ZAP-70 testing, and the number ofCLLs that express high INSR but lack other adverse prog-nostic markers associated with short TTFT. Future largestudies will be required to clarify these points.

The results of Saiya-Cork and colleagues are intriguingand raise many questions for future work: What is themechanism of INSR overexpression in CLL, and how doesit relate to 11q deletion? Is INSR overexpression truly anindependent prognostic marker? Which PI3K isoform

© 2011 American Association for Cancer Research

Pl3K Catalytic

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Figure 1. BCR signaling through the PI3K p110d isoform in CLL, leading to AKT activation. The presence of ZAP-70 in a subset of CLLsamplifies the signal downstream of the BCR. The INSR is also illustrated on the surface of the cell, signaling through PI3K, but it is unknownwhether this occursthrough p110d or p110a. Given that both the BCR and INSR pathways converge on AKT activation, CLLs that lack ZAP-70 but overexpress the INSR mayshow enhanced AKT activation compared with those that lack both ZAP-70 and INSR expression, thereby compensating for the lack of ZAP-70.

Brown

Clin Cancer Res; 17(9) May 1, 2011 Clinical Cancer Research2606

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mediates insulin signaling in CLL, and does a drug alreadyavailable for clinical trials inhibit it in vitro? Can a clinicaltrial of the most appropriate PI3K inhibitor be designedselectively for those patients with high INSR-expressingCLLs? These results provide an excellent beginning for abench-to-bedside story. . .. . .

Disclosure of Potential Conflicts of Interest

J.R. Brown has served as a consultant for Calistoga Pharmaceuticals.

Received February 24, 2011; accepted March 9, 2011; publishedOnlineFirst March 22, 2011.

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4. Austen B, Skowronska A, Baker C, Powell JE, Gardiner A, Oscier D,et al. Mutation status of the residual ATM allele is an importantdeterminant of the cellular response to chemotherapy and survivalin patients with chronic lymphocytic leukemia containing an 11qdeletion. J Clin Oncol 2007;25:5448–57.

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7. Longo PG, Laurenti L, Gobessi S, Sica S, Leone G, Efremov DG. TheAkt/Mcl-1 pathway plays a prominent role in mediating antiapoptotic

signals downstream of the B-cell receptor in chronic lymphocyticleukemia B cells. Blood 2008;111:846–55.

8. Edelman G, Bedell C, Shapiro GG, Pandya S, Kwak E, Scheffold C,et al. A phase I dose-escalation study of XL147 (SAR245408), a PI3Kinhibitor administered orally to patients (pts) with advanced malig-nancies. J Clin Oncol 2010;28:3004.

9. Furman R, Byrd J, Brown JR, Coutre S, Benson D, Wagner-JohnstonN, et al. CAL-101, an isoform-selective inhibitor of phosphatidylino-sitol 3 kinase p110d, demonstrates clinical activity and pharmacody-namic effects in patients with relapsed or refractory chroniclymphocytic leukemia. Blood 2010;116:31.

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11. Lannutti BJ, Meadows SA, Herman SE, Kashishian A, Steiner B,Johnson AJ, et al. CAL-101, a p110delta selective phosphatidyli-nositol-3-kinase inhibitor for the treatment of B-cell malignancies,inhibits PI3K signaling and cellular viability. Blood 2011;117:591–4.

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Insulin Receptor in CLL

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2011;17:2605-2607. Published OnlineFirst March 22, 2011.Clin Cancer Res   Jennifer R. Brown  Lymphocytic LeukemiaInsulin Receptor Activation in Deletion 11q Chronic

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