Sf3b1 mutations correlated to cytogenetics and mutations in notch1, fbxw7, myd88, xpo1 and tp53 in 1160 untreated cll patients

ABSTRACT We analyzed a large cohort of 1160 untreated CLL patients for novel genetic markers (_SF3B1, NOTCH1, FBXW7, MYD88, XPO1_) in the context of molecular, immunophenotypic and

cytogenetic data. _NOTCH1_ mutations (mut) (12.3%), _SF3B1_mut (9.0%) and _TP53_mut (7.1%) were more frequent than _XPO1_mut (3.4%), _FBXW7_mut (2.5%) and _MYD88_mut (1.5%). _SF3B1_mut_,

NOTCH1_mut_, TP53_mut and _XPO1_mut were highly correlated to unmutated, whereas _MYD88_mut were associated with mutated _IGHV_ status. Associations of diverse cytogenetic aberrations and

mutations emerged: (1) _SF3B1_mut with del(11q), (2) _NOTCH1_mut and _FBXW7_mut with trisomy 12 and nearly exclusiveness of _SF3B1_mut, (3) _MYD88_mut with del(13q) sole and low frequencies

of _SF3B1_mut, _NOTCH1_mut and _FBXW7_mut. In patients with normal karyotype only _SF3B1_mut were frequent, whereas _NOTCH1_mut rarely occurred. An adverse prognostic impact on time to

treatment (TTT) and overall survival (OS) was observed for _SF3B1_mut, _NOTCH1_mut and _TP53_ disruption. In multivariate analyses _SF3B1_mut, _IGHV_ mutational status and del(11q) were the

only independent genetic markers for TTT, whereas for OS _SF3B1_mut, _IGHV_ mutational status and _TP53_ disruption presented with significant impact. Finally, our data suggest that analysis

of gene mutations refines the risk stratification of cytogenetic prognostic subgroups and confirms data of a recently proposed model integrating molecular and cytogenetic data. Access

through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your institution Subscribe to this journal

Receive 12 print issues and online access $259.00 per year only $21.58 per issue Learn more Buy this article * Purchase on SpringerLink * Instant access to full article PDF Buy now Prices

may be subject to local taxes which are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support

SIMILAR CONTENT BEING VIEWED BY OTHERS _SF3B1_ MUTATED MDS: BLAST COUNT, GENETIC CO-ABNORMALITIES AND THEIR IMPACT ON CLASSIFICATION AND PROGNOSIS Article Open access 19 October 2022 GENOMIC

AND TRANSCRIPTOMIC DETERMINANTS OF CLINICAL OUTCOMES IN PATIENTS WITH AML AND _DNMT3A_ MUTATIONS Article Open access 20 May 2025 _ATM_ ABERRATIONS IN CHRONIC LYMPHOCYTIC LEUKEMIA: DEL(11Q)

RATHER THAN _ATM_ MUTATIONS IS AN ADVERSE-PROGNOSTIC BIOMARKER Article Open access 24 April 2025 REFERENCES * Ghia P, Stamatopoulos K, Belessi C, Moreno C, Stilgenbauer S, Stevenson F _et

al_. ERIC recommendations on IGHV gene mutational status analysis in chronic lymphocytic leukemia. _Leukemia_ 2007; 21: 1–3. Article  CAS  Google Scholar  * Zenz T, Krober A, Scherer K, Habe

S, Buhler A, Benner A _et al_. Monoallelic TP53 inactivation is associated with poor prognosis in chronic lymphocytic leukemia: results from a detailed genetic characterization with

long-term follow-up. _Blood_ 2008; 112: 3322–3329. Article  CAS  Google Scholar  * Dicker F, Herholz H, Schnittger S, Nakao A, Patten N, Wu L _et al_. The detection of TP53 mutations in

chronic lymphocytic leukemia independently predicts rapid disease progression and is highly correlated with a complex aberrant karyotype. _Leukemia_ 2009; 23: 117–124. Article  CAS  PubMed 

Google Scholar  * Rossi D, Cerri M, Deambrogi C, Sozzi E, Cresta S, Rasi S _et al_. The prognostic value of TP53 mutations in chronic lymphocytic leukemia is independent of Del17p13:

implications for overall survival and chemorefractoriness. _Clin Cancer Res_ 2009; 15: 995–1004. Article  CAS  Google Scholar  * Puente XS, Pinyol M, Quesada V, Conde L, Ordonez GR, Villamor

N _et al_. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. _Nature_ 2011; 475: 101–105. Article  CAS  PubMed  Google Scholar  * Wang L, Lawrence MS,

Wan Y, Stojanov P, Sougnez C, Stevenson K _et al_. SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. _N Engl J Med_ 2011; 365: 2497–2506. Article  CAS  PubMed  Google

Scholar  * Quesada V, Conde L, Villamor N, Ordonez GR, Jares P, Bassaganyas L _et al_. Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic

lymphocytic leukemia. _Nat Genet_ 2011; 44: 47–52. Article  PubMed  Google Scholar  * Fabbri G, Rasi S, Rossi D, Trifonov V, Khiabanian H, Ma J _et al_. Analysis of the chronic lymphocytic

leukemia coding genome: role of NOTCH1 mutational activation. _J Exp Med_ 2011; 208: 1389–1401. Article  CAS  PubMed  Google Scholar  * Rossi D, Bruscaggin A, Spina V, Rasi S, Khiabanian H,

Messina M _et al_. Mutations of the SF3B1 splicing factor in chronic lymphocytic leukemia: association with progression and fludarabine-refractoriness. _Blood_ 2011; 118: 6904–6908. Article

  CAS  PubMed  Google Scholar  * Oscier DG, Rose-Zerilli MJ, Winkelmann N, Gonzalez De Castro D, Gomez B, Forster J _et al_. The clinical significance of NOTCH1 and SF3B1 mutations in the UK

LRF CLL4 trial. _Blood_ 2013; 121: 468–475. Article  CAS  PubMed  Google Scholar  * Mansouri L, Cahill N, Gunnarsson R, Smedby KE, Tjonnfjord E, Hjalgrim H _et al_. NOTCH1 and SF3B1

mutations can be added to the hierarchical prognostic classification in chronic lymphocytic leukemia. _Leukemia_ 2013; 27: 512–514. Article  CAS  PubMed  Google Scholar  * Rossi D, Rasi S,

Spina V, Bruscaggin A, Monti S, Ciardullo C _et al_. Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia. _Blood_ 2013; 121:

1403–1412. Article  CAS  PubMed  Google Scholar  * Rossi D, Rasi S, Fabbri G, Spina V, Fangazio M, Forconi F _et al_. Mutations of NOTCH1 are an independent predictor of survival in chronic

lymphocytic leukemia. _Blood_ 2012; 119: 521–529. Article  CAS  PubMed  Google Scholar  * Balatti V, Bottoni A, Palamarchuk A, Alder H, Rassenti LZ, Kipps TJ _et al_. NOTCH1 mutations in CLL

associated with trisomy 12. _Blood_ 2012; 119: 329–331. Article  CAS  PubMed  Google Scholar  * Del Giudice I, Rossi D, Chiaretti S, Marinelli M, Tavolaro S, Gabrielli S _et al_. NOTCH1

mutations in +12 chronic lymphocytic leukemia (CLL) confer an unfavorable prognosis, induce a distinctive transcriptional profiling and refine the intermediate prognosis of +12 CLL.

_Haematologica_ 2012; 97: 437–441. Article  CAS  PubMed  Google Scholar  * O'Neil J, Grim J, Strack P, Rao S, Tibbitts D, Winter C _et al_. FBW7 mutations in leukemic cells mediate

NOTCH pathway activation and resistance to gamma-secretase inhibitors. _J Exp Med_ 2007; 204: 1813–1824. Article  CAS  PubMed  Google Scholar  * O'Neill LA, Bowie AG . The family of

five: TIR-domain-containing adaptors in Toll-like receptor signalling. _Nat Rev Immunol_ 2007; 7: 353–364. Article  CAS  PubMed  Google Scholar  * Dong X, Biswas A, Suel KE, Jackson LK,

Martinez R, Gu H _et al_. Structural basis for leucine-rich nuclear export signal recognition by CRM1. _Nature_ 2009; 458: 1136–1141. Article  CAS  PubMed  Google Scholar  * Swerdlow SH,

Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H _et al_ _WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues_ 4th ed. International Agency for Research on Cancer (IARC):

Lyon, 2008. Google Scholar  * Kern W, Dicker F, Schnittger S, Haferlach C, Haferlach T . Correlation of flow cytometrically determined expression of ZAP-70 using the SBZAP antibody with IgVH

mutation status and cytogenetics in 1,229 patients with chronic lymphocytic leukemia. _Cytometry B Clin Cytom_ 2009; 76: 385–393. Article  PubMed  Google Scholar  * Kern W, Bacher U,

Haferlach C, Alpermann T, Dicker F, Schnittger S _et al_. Frequency and prognostic impact of the aberrant CD8 expression in 5,523 patients with chronic lymphocytic leukemia. _Cytometry B

Clin Cytom_ 2012; 82: 145–150. Article  PubMed  Google Scholar  * Matutes E, Owusu-Ankomah K, Morilla R, Garcia MJ, Houlihan A, Que TH _et al_. The immunological profile of B-cell disorders

and proposal of a scoring system for the diagnosis of CLL. _Leukemia_ 1994; 8: 1640–1645. CAS  Google Scholar  * Matutes E, Attygalle A, Wotherspoon A, Catovsky D . Diagnostic issues in

chronic lymphocytic leukaemia (CLL). _Best Pract Res Clin Haematol_ 2010; 23: 3–20. Article  CAS  PubMed  Google Scholar  * Weissmann S, Roller A, Jeromin S, Hernandez M, Abaigar M,

Hernandez-Rivas JM _et al_. Prognostic impact and landscape of NOTCH1 mutations in chronic lymphocytic leukemia (CLL): a study on 852 patients. _Leukemia_ 2013. * Jeromin S, Haferlach T,

Grossmann V, Alpermann T, Kowarsch A, Haferlach C _et al_. High frequencies of SF3B1 and JAK2 mutations in refractory anemia with ring sideroblasts associated with marked thrombocytosis

strengthen the assignment to the category of myelodysplastic/myeloproliferative neoplasms. _Haematologica_ 2013; 98: e15–e17. Article  PubMed  Google Scholar  * Kohlmann A, Klein HU,

Weissmann S, Bresolin S, Chaplin T, Cuppens H _et al_. The Interlaboratory RObustness of Next-generation sequencing (IRON) study: a deep sequencing investigation of TET2, CBL and KRAS

mutations by an international consortium involving 10 laboratories. _Leukemia_ 2011; 25: 1840–1848. Article  CAS  PubMed  Google Scholar  * Grossmann V, Roller A, Klein HU, Weissmann S, Kern

W, Haferlach C _et al_. Robustness of amplicon deep sequencing underlines its utility in clinical applications. _J Mol Diagn_ 2013; 15: 473–484. Article  CAS  PubMed  Google Scholar  *

Dicker F, Schnittger S, Haferlach T, Kern W, Schoch C . Immunostimulatory oligonucleotide-induced metaphase cytogenetics detect chromosomal aberrations in 80% of CLL patients: a study of 132

CLL cases with correlation to FISH, IgVH status, and CD38 expression. _Blood_ 2006; 108: 3152–3160. Article  CAS  PubMed  Google Scholar  * Haferlach C, Dicker F, Schnittger S, Kern W,

Haferlach T . Comprehensive genetic characterization of CLL: a study on 506 cases analysed with chromosome banding analysis, interphase FISH, IgV(H) status and immunophenotyping. _Leukemia_

2007; 21: 2442–2451. Article  CAS  PubMed  Google Scholar  * ISCN (1995)Guidelines for cancer cytogenetics, Supplement to: An International System for Human Cytogenetic Nomenclature.

Mitelman F, Karger S (eds), 1995. * Dohner H, Stilgenbauer S, Benner A, Leupolt E, Krober A, Bullinger L _et al_. Genomic aberrations and survival in chronic lymphocytic leukemia. _N Engl J

Med_ 2000; 343: 1910–1916. Article  CAS  PubMed  Google Scholar  * Tobin G, Thunberg U, Johnson A, Thorn I, Soderberg O, Hultdin M _et al_. Somatically mutated Ig V(H)3-21 genes characterize

a new subset of chronic lymphocytic leukemia. _Blood_ 2002; 99: 2262–2264. Article  CAS  PubMed  Google Scholar  * Thorselius M, Krober A, Murray F, Thunberg U, Tobin G, Buhler A _et al_.

Strikingly homologous immunoglobulin gene rearrangements and poor outcome in VH3-21-using chronic lymphocytic leukemia patients independent of geographic origin and mutational status.

_Blood_ 2006; 107: 2889–2894. Article  CAS  Google Scholar  * Papaemmanuil E, Cazzola M, Boultwood J, Malcovati L, Vyas P, Bowen D _et al_. Somatic SF3B1 mutation in myelodysplasia with ring

sideroblasts. _N Engl J Med_ 2011; 365: 1384–1395. Article  CAS  PubMed  Google Scholar  * Weng AP, Ferrando AA, Lee W, Morris JP, Silverman LB, Sanchez-Irizarry C _et al_. Activating

mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. _Science_ 2004; 306: 269–271. Article  CAS  PubMed  Google Scholar  * Rosati E, Sabatini R, Rampino G, Tabilio A, Di IM,

Fettucciari K _et al_. Constitutively activated Notch signaling is involved in survival and apoptosis resistance of B-CLL cells. _Blood_ 2009; 113: 856–865. Article  CAS  Google Scholar  *

Orlicky S, Tang X, Willems A, Tyers M, Sicheri F . Structural basis for phosphodependent substrate selection and orientation by the SCFCdc4 ubiquitin ligase. _Cell_ 2003; 112: 243–256.

Article  CAS  PubMed  Google Scholar  * Oberg C, Li J, Pauley A, Wolf E, Gurney M, Lendahl U . The Notch intracellular domain is ubiquitinated and negatively regulated by the mammalian

Sel-10 homolog. _J Biol Chem_ 2001; 276: 35847–35853. Article  CAS  Google Scholar  * Wu G, Lyapina S, Das I, Li J, Gurney M, Pauley A _et al_. SEL-10 is an inhibitor of notch signaling that

targets notch for ubiquitin-mediated protein degradation. _Mol Cell Biol_ 2001; 21: 7403–7415. Article  CAS  PubMed  Google Scholar  * Thompson BJ, Buonamici S, Sulis ML, Palomero T,

Vilimas T, Basso G _et al_. The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia. _J Exp Med_ 2007; 204: 1825–1835. Article  CAS  PubMed  Google Scholar  * Treon SP,

Xu L, Yang G, Zhou Y, Liu X, Cao Y _et al_. MYD88 L265P somatic mutation in Waldenstrom's macroglobulinemia. _N Engl J Med_ 2012; 367: 826–833. Article  CAS  PubMed  Google Scholar  *

Ngo VN, Young RM, Schmitz R, Jhavar S, Xiao W, Lim KH _et al_. Oncogenically active MYD88 mutations in human lymphoma. _Nature_ 2011; 470: 115–119. Article  CAS  PubMed  Google Scholar  *

Schwaederle M, Ghia E, Rassenti LZ, Obara M, l' Aquila ML, Fecteau JF _et al_. Subclonal evolution involving SF3B1 mutations in chronic lymphocytic leukemia. _Leukemia_ 2013; 27:

1214–1217. Article  CAS  PubMed  Google Scholar  * Strefford JC, Sutton LA, Baliakas P, Agathangelidis A, Malcikova J, Plevova K _et al_. Distinct patterns of novel gene mutations in

poor-prognostic stereotyped subsets of chronic lymphocytic leukemia: the case of SF3B1 and subset #2. _Leukemia_ 2013. * Rossi D, Spina V, Bomben R, Rasi S, Dal-Bo M, Bruscaggin A _et al_.

Association between molecular lesions and specific B-cell receptor subsets in chronic lymphocytic leukemia. _Blood_ 2013; 121: 4902–4905. Article  CAS  Google Scholar  * Dreger P, Schnaiter

A, Zenz T, Bottcher S, Rossi M, Paschka P _et al_. TP53, SF3B1, and NOTCH1 mutations and outcome of allotransplantation for chronic lymphocytic leukemia: six-year follow-up of the GCLLSG

CLL3X trial. _Blood_ 2013; 121: 3284–3288. Article  CAS  PubMed  Google Scholar  * Shedden K, Li Y, Ouillette P, Malek SN . Characteristics of chronic lymphocytic leukemia with somatically

acquired mutations in NOTCH1 exon 34. _Leukemia_ 2012; 26: 1108–1110. Article  CAS  PubMed  Google Scholar  * Villamor N, Conde L, Martinez-Trillos A, Cazorla M, Navarro A, Bea S _et al_.

NOTCH1 mutations identify a genetic subgroup of chronic lymphocytic leukemia patients with high risk of transformation and poor outcome. _Leukemia_ 2013; 27: 1100–1106. Article  CAS  PubMed

  Google Scholar  * Pospisilova S, Gonzalez D, Malcikova J, Trbusek M, Rossi D, Kater AP _et al_. ERIC recommendations on TP53 mutation analysis in chronic lymphocytic leukemia. _Leukemia_

2012; 26: 1458–1461. Article  CAS  Google Scholar  * Landau DA, Carter SL, Stojanov P, McKenna A, Stevenson K, Lawrence MS _et al_. Evolution and impact of subclonal mutations in chronic

lymphocytic leukemia. _Cell_ 2013; 152: 714–726. Article  CAS  PubMed  Google Scholar  * Foa R, Del G I, Guarini A, Rossi D, Gaidano G . Clinical implications of the molecular genetics of

chronic lymphocytic leukemia. _Haematologica_ 2013; 98: 675–685. Article  CAS  PubMed  Google Scholar  Download references ACKNOWLEDGEMENTS We thank all co-workers in our laboratory for

their excellent technical assistance and all patients and clinicians for their participation in this study. Next-generation deep-sequencing studies were supported in part by the IRON-II

study framework (Roche Diagnostics, Penzberg, Germany). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * MLL Munich Leukemia Laboratory, Munich, Germany S Jeromin, S Weissmann, C Haferlach, F

Dicker, K Bayer, V Grossmann, T Alpermann, A Roller, A Kohlmann, T Haferlach, W Kern & S Schnittger Authors * S Jeromin View author publications You can also search for this author

inPubMed Google Scholar * S Weissmann View author publications You can also search for this author inPubMed Google Scholar * C Haferlach View author publications You can also search for this

author inPubMed Google Scholar * F Dicker View author publications You can also search for this author inPubMed Google Scholar * K Bayer View author publications You can also search for

this author inPubMed Google Scholar * V Grossmann View author publications You can also search for this author inPubMed Google Scholar * T Alpermann View author publications You can also

search for this author inPubMed Google Scholar * A Roller View author publications You can also search for this author inPubMed Google Scholar * A Kohlmann View author publications You can

also search for this author inPubMed Google Scholar * T Haferlach View author publications You can also search for this author inPubMed Google Scholar * W Kern View author publications You

can also search for this author inPubMed Google Scholar * S Schnittger View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR

Correspondence to S Schnittger. ETHICS DECLARATIONS COMPETING INTERESTS SS, WK, CH, and TH are part owners of the MLL Munich Leukemia Laboratory. SJ, SW, VG, KB, FD, TA, AR and AK are

employed by the MLL Munich Leukemia Laboratory. ADDITIONAL INFORMATION SJ and SS designed the study, interpreted the data and wrote the manuscript. SJ, SW, VG, KB, FD and AK did molecular

analyses. CH was responsible for chromosome banding and FISH analyses, WK for immunophenotyping and TH for cytomorphologic analyses. AR and TA collected and analyzed clinical data. All

authors read and contributed to the final version of the manuscript. Supplementary Information accompanies this paper on the Leukemia website SUPPLEMENTARY INFORMATION SUPPLEMENTARY FIGURE

S1 (JPG 545 KB) SUPPLEMENTARY FIGURE S2 (JPG 957 KB) SUPPLEMENTARY FIGURE S3 (JPG 1816 KB) SUPPLEMENTARY INFORMATION (DOC 299 KB) RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS

ARTICLE CITE THIS ARTICLE Jeromin, S., Weissmann, S., Haferlach, C. _et al._ _SF3B1_ mutations correlated to cytogenetics and mutations in _NOTCH1, FBXW7, MYD88, XPO1_ and _TP53_ in 1160

untreated CLL patients. _Leukemia_ 28, 108–117 (2014). https://doi.org/10.1038/leu.2013.263 Download citation * Received: 02 September 2013 * Accepted: 06 September 2013 * Published: 12

September 2013 * Issue Date: January 2014 * DOI: https://doi.org/10.1038/leu.2013.263 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get

shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * CLL *

mutation * cytogenetics * prognosis