Leveraging genomics, transcriptomics and epigenomics to understand chemoimmunotherapy resistance in chronic lymphocytic leukemia

Abstract

Patients with chronic lymphocytic leukemia (CLL) have differing clinical outcomes. Recent advances integrating multi-omic data have uncovered molecular subtypes in CLL with different prognostic implications and may allow better prediction of therapy response. While finite-duration chemoimmunotherapy (CIT) has enabled deep responses and prolonged duration of responses in the past, the advent of novel targeted therapy for the treatment of CLL has dramatically changed the therapeutic landscape. In this review, we discuss the latest genomic, transcriptomic, and epigenetic alterations regarded as major drivers of resistance to CIT in CLL. Further advances in genomic medicine will allow for better prediction of response to therapy and provide the basis for rational selection of therapy for long-term remissions with minimal toxicity.

Keywords

Chronic lymphocytic leukemia / chemoimmunotherapy / resistance

References

[1] Chen Q,Ayer T.Economic burden of chronic lymphocytic leukemia in the era of oral targeted therapies in the United States.J Clin Oncol2017;35:166-74 PMCID:PMC5559889

[2] Thompson PA,O’Brien SM.Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia.Blood2016;127:303-9 PMCID:PMC4760129

[3] Fischer K,Fink AM.Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial.Blood2016;127:208-15

[4] Eichhorst B,Kater AP.GCLLSGthe HOVON and Nordic CLL Study Groupsthe SAKKthe Israeli CLL Associationand Cancer Trials IrelandFirst-line venetoclax combinations in chronic lymphocytic leukemia.N Engl J Med2023;388:1739-54

[5] Zenz T,Busch R.TP53 mutation and survival in chronic lymphocytic leukemia.J Clin Oncol2010;28:4473-9

[6] Fischer K,Busch R.Bendamustine in combination with rituximab for previously untreated patients with chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group.J Clin Oncol2012;30:3209-16

[7] Stilgenbauer S,Paschka P.Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial.Blood2014;123:3247-54

[8] Rossi D,Deambrogi C.The prognostic value of TP53 mutations in chronic lymphocytic leukemia is independent of Del17p13: implications for overall survival and chemorefractoriness.Clin Cancer Res2009;15:995-1004

[9] Malcikova J,Rossi D.European Research Initiative on Chronic Lymphocytic Leukemia (ERIC) - TP53 networkERIC recommendations for TP53 mutation analysis in chronic lymphocytic leukemia-update on methodological approaches and results interpretation.Leukemia2018;32:1070-80 PMCID:PMC5940638

[10] Al-Sawaf O.TP53 mutations in CLL: does frequency matter?.Blood2021;138:2600-1

[11] Malcikova J,Kunt Vonkova B.Low-burden TP53 mutations in CLL: clinical impact and clonal evolution within the context of different treatment options.Blood2021;138:2670-85 PMCID:PMC8703362

[12] Rigolin GM,Quaglia FM.In CLL, comorbidities and the complex karyotype are associated with an inferior outcome independently of CLL-IPI.Blood2017;129:3495-8

[13] Raponi S,Marinelli M.Genetic landscape of ultra-stable chronic lymphocytic leukemia patients.Ann Oncol2018;29:966-72 PMCID:PMC6248613

[14] Rose-Zerilli MJ,Parker H.ATM mutation rather than BIRC3 deletion and/or mutation predicts reduced survival in 11q-deleted chronic lymphocytic leukemia: data from the UK LRF CLL4 trial.Haematologica2014;99:736-42 PMCID:PMC3971084

[15] Austen B,Baker C.Mutation status of the residual ATM allele is an important determinant of the cellular response to chemotherapy and survival in patients with chronic lymphocytic leukemia containing an 11q deletion.J Clin Oncol2007;25:5448-57

[16] Herling CD,Rocha CK.Complex karyotypes and KRAS and POT1 mutations impact outcome in CLL after chlorambucil-based chemotherapy or chemoimmunotherapy.Blood2016;128:395-404

[17] Ramsay AJ,Foronda M.POT1 mutations cause telomere dysfunction in chronic lymphocytic leukemia.Nat Genet2013;45:526-30

[18] Asslaber D,Leisch M.BIRC3 expression predicts CLL progression and defines treatment sensitivity via enhanced NF-κB nuclear translocation.Clin Cancer Res2019;25:1901-12

[19] Diop F,Favini C.Biological and clinical implications of BIRC3 mutations in chronic lymphocytic leukemia.Haematologica2020;105:448-56 PMCID:PMC7012473

[20] Kater AP,Chyla B.Response in patients with BIRC3-mutated relapsed/refractory chronic lymphocytic leukemia treated with fixed-duration venetoclax and rituximab.Haematologica2020;105:e382-3 PMCID:PMC7327665

[21] Tausch E,Schlenk RF.Prognostic and predictive role of gene mutations in chronic lymphocytic leukemia: results from the pivotal phase III study COMPLEMENT1.Haematologica2020;105:2440-7 PMCID:PMC7556677

[22] Nadeu F,Royo C.Clinical impact of clonal and subclonal TP53, SF3B1, BIRC3, NOTCH1, and ATM mutations in chronic lymphocytic leukemia.Blood2016;127:2122-30 PMCID:PMC4912011

[23] Fabbri G,Viganotti M.Common nonmutational NOTCH1 activation in chronic lymphocytic leukemia.Proc Natl Acad Sci U S A2017;114:E2911-9 PMCID:PMC5389283

[24] Rossi D,Fabbri G.Mutations of NOTCH1 are an independent predictor of survival in chronic lymphocytic leukemia.Blood2012;119:521-9 PMCID:PMC3257017

[25] Balatti V,Palamarchuk A.NOTCH1 mutations in CLL associated with trisomy 12.Blood2012;119:329-31 PMCID:PMC3257004

[26] Sutton LA,Baliakas P.ERICthe European Research Initiative on CLLDifferent spectra of recurrent gene mutations in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors.Haematologica2016;101:959-67 PMCID:PMC4967575

[27] Edelmann J,Vilventhraraja E.Rituximab and obinutuzumab differentially hijack the B cell receptor and NOTCH1 signaling pathways.iScience2021;24:102089 PMCID:PMC7878992

[28] Estenfelder S,Robrecht S.Gene mutations and treatment outcome in the context of chlorambucil (Clb) without or with the addition of Rituximab (R) or Obinutuzumab (GA-101, G) - results of an extensive analysis of the phase III study CLL11 of the German CLL Study Group.Blood2016;128:3227

[29] Close V,Kugler SJ.FBXW7 mutations reduce binding of NOTCH1, leading to cleaved NOTCH1 accumulation and target gene activation in CLL.Blood2019;133:830-9

[30] Rossi D.FBXW7 is a biologically validated cancer driver gene for CLL.Blood2019;133:774-6

[31] De Paoli L,Monti S.MGA, a suppressor of MYC, is recurrently inactivated in high risk chronic lymphocytic leukemia.Leuk Lymphoma2013;54:1087-90

[32] Hurlin PJ,Copeland NG,Eisenman RN.Mga, a dual-specificity transcription factor that interacts with Max and contains a T-domain DNA-binding motif.EMBO J2000;19:3841-2

[33] Rossi D,Spina V.Mutations of the SF3B1 splicing factor in chronic lymphocytic leukemia: association with progression and fludarabine-refractoriness.Blood2011;118:6904-8 PMCID:PMC3245210

[34] Wan Y.SF3B1 mutations in chronic lymphocytic leukemia.Blood2013;121:4627-34 PMCID:PMC3674664

[35] Wang L,Fan J.Transcriptomic characterization of SF3B1 mutation reveals its pleiotropic effects in chronic lymphocytic leukemia.Cancer Cell2016;30:750-63 PMCID:PMC5127278

[36] Yin S,Sun J.A murine model of chronic lymphocytic leukemia based on B cell-restricted expression of Sf3b1 mutation and atm deletion.Cancer Cell2019;35:283-96.e5 PMCID:PMC6372356

[37] Walker JS,Harrington B.Recurrent XPO1 mutations alter pathogenesis of chronic lymphocytic leukemia.J Hematol Oncol2021;14:17 PMCID:PMC7809770

[38] Cosson A,Bougacha N.Gain in the short arm of chromosome 2 (2p+) induces gene overexpression and drug resistance in chronic lymphocytic leukemia: analysis of the central role of XPO1.Leukemia2017;31:1625-9

[39] Taylor J,Gorelick AN.Altered nuclear export signal recognition as a driver of oncogenesis.Cancer Discov2019;9:1452-67 PMCID:PMC6774834

[40] Landau DA,Taylor-Weiner AN.Mutations driving CLL and their evolution in progression and relapse.Nature2015;526:525-30 PMCID:PMC4815041

[41] Ljungström V,Young E.Whole-exome sequencing in relapsing chronic lymphocytic leukemia: clinical impact of recurrent RPS15 mutations.Blood2016;127:1007-16 PMCID:PMC4768426

[42] Bretones G,Arango JR.Altered patterns of global protein synthesis and translational fidelity in RPS15-mutated chronic lymphocytic leukemia.Blood2018;132:2375-88 PMCID:PMC6410914

[43] Gutierrez C,Fu D.RPS15 and TP53 co-mutation drives B cell malignancy through altered translation and MYC activation in a murine model.Blood2020;136:28-9

[44] Vendramini E,Pozzo F.KRAS, NRAS, and BRAF mutations are highly enriched in trisomy 12 chronic lymphocytic leukemia and are associated with shorter treatment-free survival.Leukemia2019;33:2111-5 PMCID:PMC6756038

[45] Ghia P,Belessi C.European Research Initiative on CLLERIC recommendations on IGHV gene mutational status analysis in chronic lymphocytic leukemia.Leukemia2007;21:1-3

[46] Eichhorst B,Bahlo J.international group of investigatorsGerman CLL Study Group (GCLLSG)First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial.Lancet Oncol2016;17:928-42

[47] Langerak AW,Goede V.Prognostic value of MRD in CLL patients with comorbidities receiving chlorambucil plus obinutuzumab or rituximab.Blood2019;133:494-7 PMCID:PMC6356981

[48] Knisbacher BA,Hahn CK.Molecular map of chronic lymphocytic leukemia and its impact on outcome.Nat Genet2022;54:1664-74 PMCID:PMC10084830

[49] Herling CD,Benner A.Time-to-progression after front-line fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy for chronic lymphocytic leukaemia: a retrospective, multicohort study.Lancet Oncol2019;20:1576-86 PMCID:PMC7147008

[50] Ferracin M,Rizzotto L.MicroRNAs involvement in fludarabine refractory chronic lymphocytic leukemia.Mol Cancer2010;9:123 PMCID:PMC2892453

[51] Ferrajoli A,Ivan C.Prognostic value of miR-155 in individuals with monoclonal B-cell lymphocytosis and patients with B chronic lymphocytic leukemia.Blood2013;122:1891-9 PMCID:PMC3779381

[52] Zenz T,Eldering E.miR-34a as part of the resistance network in chronic lymphocytic leukemia.Blood2009;113:3801-8

[53] He L,Lowe SW.microRNAs join the p53 network - another piece in the tumour-suppression puzzle.Nat Rev Cancer2007;7:819-22 PMCID:PMC4053212

[54] Calin GA,Sevignani C.MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukemias.Proc Natl Acad Sci U S A2004;101:11755-60 PMCID:PMC511048

[55] Wang L,Wan Y.SF3B1 and other novel cancer genes in chronic lymphocytic leukemia.N Engl J Med2011;365:2497-506 PMCID:PMC3685413

[56] Shuai S,Diaz-Navarro A.The U1 spliceosomal RNA is recurrently mutated in multiple cancers.Nature2019;574:712-6

[57] Wu Y,Fernandez M.METTL3-mediated m6A modification controls splicing factor abundance and contributes to aggressive CLL.Blood Cancer Discov2023;4:228-45 PMCID:PMC10150290

[58] Herbst SA,Helmboldt AJ.Proteogenomics refines the molecular classification of chronic lymphocytic leukemia.Nat Commun2022;13:6226 PMCID:PMC9584885

[59] Kulis M,Bibikova M.Epigenomic analysis detects widespread gene-body DNA hypomethylation in chronic lymphocytic leukemia.Nat Genet2012;44:1236-42

[60] Oakes CC,Assenov Y.DNA methylation dynamics during B cell maturation underlie a continuum of disease phenotypes in chronic lymphocytic leukemia.Nat Genet2016;48:253-64 PMCID:PMC4963005

[61] Queirós AC,Clot G.A B-cell epigenetic signature defines three biologic subgroups of chronic lymphocytic leukemia with clinical impact.Leukemia2015;29:598-605

[62] Nadeu F,Clot G.IGLV3-21R110 identifies an aggressive biological subtype of chronic lymphocytic leukemia with intermediate epigenetics.Blood2021;137:2935-46 PMCID:PMC8191863

[63] Duran-Ferrer M,Nadeu F.The proliferative history shapes the DNA methylome of B-cell tumors and predicts clinical outcome.Nat Cancer2020;1:1066-81 PMCID:PMC8168619

[64] Barrow TM,Lafta F.Epigenome-wide analysis reveals functional modulators of drug sensitivity and post-treatment survival in chronic lymphocytic leukaemia.Br J Cancer2021;124:474-83 PMCID:PMC7852668

[65] Gruber M,Leshchiner I.Growth dynamics in naturally progressing chronic lymphocytic leukaemia.Nature2019;570:474-9 PMCID:PMC6630176

[66] Landau DA,Rosebrock D.The evolutionary landscape of chronic lymphocytic leukemia treated with ibrutinib targeted therapy.Nat Commun2017;8:2185 PMCID:PMC5736707

[67] Kittai AS,Goldstein D.The impact of increasing karyotypic complexity and evolution on survival in patients with CLL treated with ibrutinib.Blood2021;138:2372-82