Preferential Genetic Pathways Lead to Relapses in Adult B-Cell Acute Lymphoblastic Leukemia

被引：0

作者：

Navas-Acosta, Josgrey ^{[1
]}

Hernandez-Sanchez, Alberto ^{[1
,2
]}

Gonzalez, Teresa ^{[1
,2
]}

Villaverde Ramiro, Angela ^{[1
]}

Santos, Sandra ^{[1
]}

Miguel, Cristina ^{[1
]}

Ribera, Jordi ^{[3
]}

Granada, Isabel ^{[3
]}

Morgades, Mireia ^{[3
]}

Sanchez, Ricardo ^{[4
]}

Such, Esperanza ^{[5
]}

Barrena, Susana ^{[6
]}

Ciudad, Juana ^{[6
]}

Davila, Julio ^{[7
]}

de las Heras, Natalia ^{[8
]}

Garcia-de Coca, Alfonso ^{[9
]}

Labrador, Jorge ^{[10
]}

Queizan, Jose Antonio ^{[11
]}

Martin, Sandra ^{[12
]}

Orfao, Alberto ^{[6
]}

Ribera, Josep-Maria ^{[3
]}

Benito, Rocio ^{[1
]}

Hernandez-Rivas, Jesus Maria ^{[1
,2
,13
]}

机构：

[1] Univ Salamanca, Ctr Invest Canc, IBSAL, IBMCC,CSIC, Salamanca 37007, Spain

[2] Complejo Asistencial Univ Salamanca, Dept Hematol, Salamanca 37007, Spain

[3] ICO Hosp Germans Trias i Pujol, Inst Recerca Leucemia Josep Carreras IJC, Badalona 08916, Spain

[4] Hosp Doce Octubre Hosp, Dept Hematol, Madrid 28041, Spain

[5] Hosp Univ & Politecn La Fe, Dept Hematol, Valencia 46026, Spain

[6] Univ Salamanca, Dept Cytometry, Salamanca 37007, Spain

[7] Hosp Nuestra Senora Sonsoles, Serv Hematol, Avila 05004, Spain

[8] Hosp Univ Leon, Serv Hematol, Leon 24071, Spain

[9] Hosp Clin Valladolid, Dept Hematol, Valladolid 47003, Spain

[10] Hosp Univ Burgos, Dept Hematol, Burgos 09006, Spain

[11] Hosp Gen Segovia, Dept Hematol, Segovia 40002, Spain

[12] Hosp Reg Univ Malaga, Mol Biol Unit, Malaga 29010, Spain

[13] Univ Salamanca, Dept Med, Salamanca 37007, Spain

来源：

CANCERS | 2024年 / 16卷 / 24期

关键词：

B-cell ALL; relapse; NGS; mutational dynamics; IZKF1 (plus); RAS mutations; TP53; KINASE DOMAIN MUTATIONS; COPY NUMBER ALTERATIONS; TP53; MUTATIONS; PRECURSOR; THERAPY; CHEMOTHERAPY; RESISTANCE; LANDSCAPE; CORRELATE;

D O I：

10.3390/cancers16244200

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Adult B-cell acute lymphoblastic leukemia (B-ALL) is characterized by genetic heterogeneity and a high relapse rate, affecting over 40% of adults. However, the mechanisms leading to relapse in adults are poorly understood. Forty-four adult B-ALL patients were studied at both diagnosis and relapse by next-generation sequencing (NGS). Four main genetic pathways leading to relapse in adults were identified: IKZF1(plus) genetic profile, RAS mutations and TP53 alterations in Ph-negative B-ALL and acquisition of ABL1 mutations in Ph-positive patients. The most frequently deleted gene at diagnosis was IKZF1 (52%), and 70% of these patients had IKZF1(plus) profile. Notably, 88% of patients with IKZF1(plus) at diagnosis retained this genetic profile at relapse. Conversely, the acquisition of RAS mutations or the expansion of subclones (normalized variant allele frequency < 25%) present from diagnosis were observed in 24% of Ph-negative patients at relapse. In addition, 24% of relapses in the Ph-negative cohort could potentially be driven by TP53 alterations. Of these cases, five presented from diagnosis, and four emerged at relapse, mostly as "double-hit" events involving both TP53 deletion and mutation. In Ph-positive B-ALL, the main genetic finding at relapse was the acquisition of ABL1 mutations (86%). Three clonal evolution patterns were identified: the persistent clone trajectory (25%), the expanding clone trajectory (11%) and the therapy-boosted trajectory (48%). Our results reveal the presence of preferential biological pathways leading to relapse in adult B-ALL. These findings underscore the need for personalized therapeutic strategies to improve clinical outcomes in adult patients with B-ALL.

引用

页数：15

共 50 条

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