Mutations of the SF3B1 splicing factor in chronic lymphocytic leukemia: association with progression and fludarabine-refractoriness

被引：309

作者：

Rossi, Davide ^{[3
]}

Bruscaggin, Alessio ^{[3
]}

Spina, Valeria ^{[3
]}

Rasi, Silvia ^{[3
]}

Khiabanian, Hossein ^{[4
,5
]}

Messina, Monica ^{[1
,2
]}

Fangazio, Marco ^{[3
]}

Vaisitti, Tiziana ^{[6
,7
]}

Monti, Sara ^{[3
]}

Chiaretti, Sabina ^{[8
]}

Guarini, Anna ^{[8
]}

Del Giudice, Ilaria ^{[8
]}

Cerri, Michaela ^{[3
]}

Cresta, Stefania ^{[3
]}

Deambrogi, Clara ^{[3
]}

Gargiulo, Ernesto ^{[3
]}

Gattei, Valter ^{[9
]}

Forconi, Francesco ^{[10
]}

Bertoni, Francesco ^{[11
]}

Deaglio, Silvia ^{[6
,7
]}

Rabadan, Raul ^{[4
,5
]}

Pasqualucci, Laura ^{[1
,2
,12
,13
]}

Foa, Robin ^{[8
,14
]}

Dalla-Favera, Riccardo ^{[1
,2
,12
,15
,16
]}

Gaidano, Gianluca ^{[3
]}

机构：

[1] Columbia Univ, Inst Canc Genet, New York, NY 10032 USA

[2] Columbia Univ, Herbert Irving Comprehens Canc Ctr, New York, NY 10032 USA

[3] Amedeo Avogadro Univ Eastern Piedmont, Dept Clin & Expt Med, Div Hematol, Novara, Italy

[4] Columbia Univ, Dept Biomed Informat, New York, NY 10032 USA

[5] Columbia Univ, Ctr Computat Biol & Bioinformat, New York, NY 10032 USA

[6] Univ Turin, Dept Genet Biol & Biochem, Turin, Italy

[7] Univ Turin, Human Genet Fdn, Turin, Italy

[8] Univ Roma La Sapienza, Dept Cellular Biotechnol & Hematol, Div Hematol, Rome, Italy

[9] Ist Ricovero & Cura Carattere Sci, Ctr Riferimento Oncol, Aviano, Italy

[10] Univ Siena, Div Hematol, I-53100 Siena, Italy

[11] Ist Oncol Svizzera Italiana, Oncol Inst So Switzerland, Bellinzona, Switzerland

[12] Columbia Univ, Dept Pathol & Cell Biol, New York, NY 10032 USA

[13] Univ Perugia, Inst Hematol, I-06100 Perugia, Italy

[14] Univ Roma La Sapienza, Fdn Eleonora Lorillard Spencer Cenci, Rome, Italy

[15] Columbia Univ, Dept Genet & Dev, New York, NY 10032 USA

[16] Columbia Univ, Dept Microbiol & Immunol, New York, NY 10032 USA

来源：

BLOOD | 2011年 / 118卷 / 26期

关键词：

PRE-MESSENGER-RNA; PROTEIN; SPLICEOSTATIN; SURVIVAL; REPEATS; DISEASE; SAPS;

D O I：

10.1182/blood-2011-08-373159

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

The genetic lesions identified in chronic lymphocytic leukemia (CLL) do not entirely recapitulate the disease pathogenesis and the development of serious complications, such as chemorefractoriness. While investigating the coding genome of fludarabine-refractory CLL, we observed that mutations of SF3B1, encoding a splicing factor and representing a critical component of the cell spliceosome, were recurrent in 10 of 59 (17%) fludarabine-refractory cases, with a frequency significantly greater than that observed in a consecutive CLL cohort sampled at diagnosis (17/301, 5%; P = .002). Mutations were somatically acquired, were generally represented by missense nucleotide changes, clustered in selected HEAT repeats of the SF3B1 protein, recurrently targeted 3 hotspots (codons 662, 666, and 700), and were predictive of a poor prognosis. In fludarabine-refractory CLL, SF3B1 mutations and TP53 disruption distributed in a mutually exclusive fashion (P = .046). The identification of SF3B1 mutations points to splicing regulation as a novel pathogenetic mechanism of potential clinical relevance in CLL. (Blood. 2011;118(26):6904-6908)

引用

页码：6904 / 6908

页数：5

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