MUTACIONES DEL GEN NOTCH1 EN LA LEUCEMIA LINFOCITICA CRONICA

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La leucemia linfocítica crónica es la leucemia más frecuente en adultos de Occidente. Presenta un curso clínico altamente variable, con pacientes que requieren tratamiento inmediato y otros con un curso indolente de la enfermedad. Nuestro objetivo fue evaluar mutaciones de NOTCH1 en nuestros pacientes mediante ASO-PCR y secuenciación.
Autor:
Camila Galvano
Columnista Experta de SIIC

Institución:
Instituto de Medicina Experimental, CONICET-Academia Nacional de Medicina


Artículos publicados por Camila Galvano
Coautores
Patricia Dos Santos* Carmen Stanganelli** Irma Slavutsky*** 
Licenciada en Genética, Instituto de Medicina Experimental, CONICET-Academia Nacional de Medicina, CABA, Argentina*
Bioquímica, Instituto de Investigaciones Hematológicas, Academia Nacional de Medicina, CABA, Argentina**
Médica, Instituto de Medicina Experimental, CONICET-Academia Nacional de Medicina, CABA, Argentina***
Recepción del artículo
3 de Junio, 2019
Aprobación
3 de Junio, 2019
Primera edición
29 de Julio, 2019
Segunda edición, ampliada y corregida
7 de Junio, 2021

Resumen
La leucemia linfocítica crónica (LLC) es la leucemia más frecuente en adultos de Occidente. Presenta un curso clínico altamente variable, con pacientes que requieren tratamiento inmediato y otros con un curso indolente de la enfermedad. Los estudios genéticos constituyen herramientas de suma utilidad en esta enfermedad, encontrándose incorporados a las clasificaciones de riesgo internacionales. El análisis de los rearreglos genómicos y del estado mutacional de los genes IGHV (immunoglobulin heavy chain variable region) ha hecho factible establecer grupos de riesgo de alto valor pronóstico. Más recientemente, estudios de secuenciación de última generación permitieron la detección de mutaciones somáticas previamente desconocidas en esta afección, que podrían explicar la amplia variabilidad clínica observada en la LLC. Entre ellas, resultan de interés las observadas en el gen NOTCH1 (neurogenic locus notch homolog protein 1), cuya desregulación se asocia con el desarrollo tumoral. Estas mutaciones se acumulan en mayor medida en el exón 34 (80% de los casos) y en la región 3´UTR (untraslated region), lo que genera codones de terminación prematuros que originan una proteína NOTCH1 constitutivamente activa y más estable, los cuales se asocian con pronóstico adverso y refractariedad al tratamiento. Nuestro objetivo fue evaluar mutaciones de NOTCH1 en nuestros pacientes mediante ASO-PCR y secuenciación. Se detectaron mutaciones en el 4.4% de los casos, valor concordante con los datos internacionales (5% a 10%). Su inclusión en la caracterización genética de los pacientes con LLC permitirá refinar la categorización de los grupos de riesgo, aspecto de suma importancia tanto en el seguimiento clínico como en la toma de decisiones terapéuticas.

Palabras clave
gen NOTCH1, mutaciones, leucemia linfocítica crónica, citogenética, FISH, IgH


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Abstract
Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world. The disease has a highly variable clinical course, ranging from very indolent cases to patients with aggressive and rapidly progressing outcome. Genetic studies are useful tools in analyzing this pathology, and have been incorporated in international risk classifications. The analysis of genomic rearrangements and the mutational status of immunoglobulin heavy chain variable have allowed risk groups of high prognostic value to be established. More recently, next generation sequencing studies have identified novel somatic mutations that could explain the wide clinical variability of this pathology. Among them, the analysis of NOTCH1 (neurogenic locus notch homolog protein 1) gene mutations are of interest, as deregulation is associated with tumorigenesis.
NOTCH1 mutations are mostly located at exon 34 (80% of cases) and 3´UTR (untranslated region). They produce premature stop codons that produce a constitutively active and stable NOTCH1 protein. NOTCH1 mutations are associated with adverse prognosis and refractoriness to treatment. The aim of this study was to analyze NOTCH1 mutations in CLL patients by ASO-PCR and sequencing. Our results found 4.4% of cases with NOTCH1 mutated values concordant with international observations (5%-10%). Including them in the genetic status of CLL patients allows the characterization of risk groups, an aspect of great importance in clinical practice and therapeutic decisions, to be refined.

Key words
NOTCH1 gene, mutations, chronic lymphocytic leukemia, cytogenetics, FISH, IgH


Clasificación en siicsalud
Artículos originales > Expertos de Iberoamérica >
página   www.siicsalud.com/des/expertocompleto.php/

Especialidades
Principal: Genética Humana, Hematología
Relacionadas: Diagnóstico por Laboratorio, Oncología



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Irma Slavutsky, 1425, Pacheco de Melo 3081, CABA, Argentina
Bibliografía del artículo
1. Chiorazzi N, Rai KR, Ferrarini M. Chronic lymphocytic leukemia. N Engl J Med 352:804-815, 2005.
2. Hallek M. Chronic lymphocytic leukemia: 2017 update on diagnosis, risk stratification, and treatment. Am J Hematol 92:946-965, 2017.
3. Damle RN, Calissano C, Chiorazzi N. Chronic lymphocytic leukaemia: a disease of activated monoclonal B cells. Best Pract Res Clin Haematol 23:33-45, 2010.
4. Palacios F, Abreu C, Prieto D, et al. Activation of the PI3K/AKT pathway by microRNA-22 results in CLL B-cell proliferation. Leukemia 29:115-25, 2015.
5. Dighiero D, Hamblin TJ. Chronic lymphocytic leukaemia. Lancet 371:1017-1029, 2008.
6. Gaidano G, Rossi D. The mutational landscape of chronic lymphocytic leukemia and its impact on prognosis and treatment. Hematology Am Soc Hematol Educ Program 2017:329-337, 2017.
7. Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK. Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 96:1848-1854, 1999.
8. Damle RN, Wasil T, Fais F, et al. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 94:1840-1847, 1999.
9. Stamatopoulos K, Belessi C, Hadzidimitriou A, et al. Immunoglobulin light chain repertoire in chronic lymphocytic leukemia. Blood 106:3575-3583, 2005.
10. 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 21:2442-2451, 2007.
11. Travella A, Ripollés L, Aventin A, et al. Structural alterations in chronic lymphocytic leukaemia. Cytogenetic and FISH analysis. Hematol Oncol 31:79-87, 2013.
12. Döhner H, Stilgenbauer S, Benner A, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 343:1910-1916, 2000.
13. Van Dyke DL, Werner L, Rassenti LZ, et al. The Dohner fluorescence in situ hybridization prognostic classification of chronic lymphocytic leukaemia (CLL): the CLL Research Consortium experience. Br J Haematol 173:105-113, 2016.
14. Gazzola A, Mannu C1, Rossi M, et al. The evolution of clonality testing in the diagnosis and monitoring of hematological malignancies. Ther Adv Hematol 5:35-47, 2014.
15. Baliakas P, Hadzidimitriou A, Sutton LA, et al. Recurrent mutations refine prognosis in chronic lymphocytic leukemia. Leukemia 29:329-336, 2015.
16. Malcikova J, Stano-Kozubik K, Tichy B, et al. Detailed analysis of therapy-driven clonal evolution of TP53 mutations in chronic lymphocytic leukemia. Leukemia 29:877-885, 2015.
17. Rosati E, Sabatini R, Rampino G, et al. Constitutively activated Notch signaling is involved in survival and apoptosis resistance of B-CLL cells. Blood 22:856-865, 2009.
18. Lobry C, Oh P, Aifantis I. Oncogenic and tumor suppressor functions of Notch in cancer: it's NOTCH what you think. J Exp Med 26:1931-1935, 2011.
19. Leong KG, Karsan A. Recent insights into the role of Notch signaling in tumorigenesis. Blood 107:2223-2233, 2006.
20. Hajdu M, Sebestyén A, Barna G, et al. Activity of the notch-signalling pathway in circulating human chronic lymphocytic leukaemia cells. Scand J Immunol 65:271-275, 2007.
21. Osborne BA. B-CLL kicks it up a Notch. Blood 22:765-766, 2009.
22. Liu N, Zhang J, Ji C. The emerging roles of Notch signaling in leukemia and stem cells. Biomark Res 1:23, 2013.
23. Rothenberg EV. T cell lineage commitment: identity and renunciation. J Immunol 186:6649-6655, 2011.
24. Rosati E, Baldoni S, De Falco F, et al. NOTCH1 Aberrations in Chronic Lymphocytic Leukemia. Front Oncol 8:229, 2018.
25. Di Ianni M, Baldoni S, Del Papa B, et al. NOTCH1 Is Aberrantly Activated in Chronic Lymphocytic Leukemia Hematopoietic Stem Cells. Front Oncol 8:105, 2018.
26. Arruga F, Gizdic B, Serra S, et al. Functional impact of NOTCH1 mutations in chronic lymphocytic leukemia. Leukemia 28:1060-1070, 2014.
27. Rossi D, Rasi S, Fabbri G, et al. Mutations of NOTCH1 are an independent predictor of survival in chronic lymphocytic leukemia. Blood 119:521-529, 2012.
28. Gianfelici V. Activation of the NOTCH1 pathway in chronic lymphocytic leukemia. Haematologica 97:328-330, 2012.
29. Puente XS, Beà S, Valdés-Mas R, et al. Non-coding recurrent mutations in chronic lymphocytic leukaemia. Nature 526:519-524, 2015.
30. Abramenko IV, Bilous NI, Chumak AA, Dyagil IS, Martina ZV. Analysis of the 3'UTR region of the NOTCH1 gene in chronic lymphocytic leukemia patients. Exp Oncol 40:211-217, 2018.
31. Fabbri G, Rasi S, Rossi D, et al. Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation. J Exp Med 208:1389-1401, 2011.
32. Zou Y, Fan L, Xia Y, et al. NOTCH1 mutation and its prognostic significance in Chinese chronic lymphocytic leukemia: a retrospective study of 317 cases. Cancer Med 7:1689-1696, 2018.
33. Xu ZS, Zhang JS, Zhang JY, et al. Constitutive activation of NF-? signaling by NOTCH1 mutations in chronic lymphocytic leukemia. Oncol Rep 33:1609-1614, 2015.
34. Albi E, Baldoni S, Aureli P, et al. Ibrutinib treatment of a patient with relapsing chronic lymphocytic leukemia and sustained remission of Richter syndrome. Tumori 103:37-40, 2017.
35. Rossi D, Spina V, Forconi F, et al. Molecular history of Richter syndrome: origin from a cell already present at the time of chronic lymphocytic leukemia diagnosis. Int J Cancer 130:3006-3010, 2011.
36. Del Giudice I, Rossi D, Chiaretti 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 97:437-441, 2012.
37. Rasi S, Monti S, Spina V, Foà R, Gaidano G, Rossi D. NOTCH1 mutations in monoclonal B-cell lymphocytosis. Hematologica 97:153-154, 2012.
38. Nadeu F, Delgado J, Royo C, et al. Clinical impact of clonal and subclonal TP53, SF3B1, BIRC3, NOTCH1, and ATM mutations in chronic lymphocytic leukemia. Blood 127:2122-2130, 2016.
39. Rasi S, Khiabanian H, Ciardullo C, et al. Clinical impact of small subclones harboring NOTCH1, SF3B1 or BIRC3 mutations in chronic lymphocytic leukemia. Haematologica 101:135-138, 2016.
40. Fabbri G, Holmes AB, Viganotti M, et al. Common nonmutational NOTCH1 activation in chronic lymphocytic leukemia. Proc Natl Acad Sci USA 114:2911-2919, 2017.
41. 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 18:108-117, 2014.
42. Balatti V, Bottoni A, Palamarchuk A, et al. NOTCH1 mutations in CLL associated with trisomy 12. Blood 119:329-331, 2012.
43. Sutton LA, Young E, Baliakas P, et al. Different spectra of recurrent gene mutations in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors. Hematologica 101:959-967, 2016.
44. Dal Bo M, Del Principe MI, Pozzo F, et al. NOTCH1 mutations identify a chronic lymphocytic leukemia patient subset with worse prognosis in the setting of a rituximab-based induction and consolidation treatment. Ann Hematol 93:1765-1774, 2014.
45. Sportoletti P, Baldoni S, Cavalli L, et al. NOTCH1 PEST domain mutation is an adverse prognostic factor in B-CLL. Br J Haematol 151:404-406, 2010.
46. Sportoletti P, Baldoni S, Del Papa B, et al. A revised NOTCH1 mutation frequency still impacts survival while the allele burden predicts early progression in chronic lymphocytic leukemia. Leukemia 28:436-439, 2014.
47. Guièze R, Robbe P, Clifford R, et al. Presence of multiple recurrent mutations confers poor trial outcome of relapsed/refractory CLL. Blood 126:2110-2117, 2015.
48. Putowski M, Podgórniak M, Piróg M, et al. Prognostic impact of NOTCH1, MYD88, and SF3B1 mutations in Polish patients with chronic lymphocytic leukemia. Pol Arch Intern Med 127:238-244, 2017.
49. Del Poeta G, Del Principe MI, Postorino M, et al. Apoptosis resistance and NOTCH1 mutations impair clinical outcome in chronic lymphocytic leukemia (CLL) patients treated with ibrutinib. Blood 130(Suppl 1):261, 2017.
50. Brown JR, Hillmen P, O'Brien S, et al. Extended follow-up and impact of high-risk prognostic factors from the phase 3 RESONATE study in patients with previously treated CLL/SLL. Leukemia 32:83-91, 2018.
51. Stilgenbauer S, Schnaiter A, Paschka P, et al. Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial. Blood 123:3247-3254, 2014.
52. Rai KR, Sawitsky A. A review of the prognostic role of cytogenetic, phenotypic, morphologic, and immune function characteristics in chronic lymphocytic leukemia. Blood Cells 12:327-38, 1987.
53. Lionetti M, Fabris S, Cutrona G, et al. High-throughput sequencing for the identification of NOTCH1 mutations in early stage chronic lymphocytic leukaemia: biological and clinical implications. Br J Haematol 165:629-639, 2014.
54. Palmitelli M, Stanganelli C, Stella F, et al. Analysis of basal chromosome instability in patients with chronic lymphocytic leukaemia. Mutagenesis 2019. doi: 10.1093/mutage/gez009.
55. Stanganelli C, Travella A, Bezares R, Slavutski I. Immunoglobulin gene rearrangements and mutational status in Argentinean patients with chronic lymphocytic leukemia. Clin Lymph, Myeloma Leuk 13:447-457, 2013.
56. Weissmann S, Roller A, Jeromin S, et al. Prognostic impact and landscape of NOTCH1 mutations in chronic lymphocytic leukemia (CLL): a study on 852 patients. Leukemia 27:2393-2396, 2013.
57. Rossi D, Rasi S, Spina V, et al. Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia. Blood 121:1403-1412, 2013.
58. Baldoni S, Del Papa B, Dorillo E, et al. Bepridil exhibits anti-leukemic activity associated with NOTCH1 pathway inhibition in chronic lymphocytic leukemia. Int J Cancer 143:958-970, 2018.

 
 
 
 
 
 
 
 
 
 
 
 
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