Clinico-genomic profiling and clonal dynamic modeling of TP53-aberrant myelodysplastic syndrome and acute myeloid leukemia

被引：29

作者：

Patel, Shyam A. ^{[1
]}

Lloyd, Maxwell R. ^{[2
]}

Cerny, Jan ^{[1
]}

Shi, Qiming ^{[1
,3
]}

Simin, Karl ^{[4
]}

Ediriwickrema, Asiri ^{[5
]}

Hutchinson, Lloyd ^{[6
]}

Miron, Patricia M. ^{[6
]}

Higgins, Anne W. ^{[6
]}

Ramanathan, Muthalagu ^{[1
]}

Gerber, Jonathan M. ^{[1
]}

机构：

[1] Univ Massachusetts, UMass Mem Med Ctr, Dept Med Hematol & Oncol, Med Sch, 55 Lake Ave North, Worcester, MA 01655 USA

[2] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA

[3] Univ Massachusetts, Dept Populat & Quantitat Hlth Sci, Med Sch, Worcester, MA 01655 USA

[4] Univ Massachusetts, Dept Mol Cell & Canc Biol, Med Sch, Worcester, MA 01655 USA

[5] Stanford Univ, Inst Stem Cell Biol & Regenerat Med, Dept Med, Div Hematol, Stanford, CA 94305 USA

[6] Univ Massachusetts, UMass Mem Med Ctr, Dept Pathol, Med Sch, Worcester, MA 01655 USA

来源：

LEUKEMIA & LYMPHOMA | 2021年 / 62卷 / 14期

关键词：

Myelodysplastic syndrome; acute myeloid leukemia; TP53; hematopoietic stem cell; clonal dynamics; hypomethylating agents; COMPLEX KARYOTYPE; P53; MUTATIONS; CANCER; TP53; DATABASE; IMPACT; ADULTS; AML;

D O I：

10.1080/10428194.2021.1957869

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

TP53-aberrant myelodysplastic syndrome and acute myeloid leukemia have dismal outcomes. Here, we define the clinico-genomic landscape of TP53 disruptions in 40 patients and employ clonal dynamic modeling to map the mutational hierarchy against clinical outcomes. Most TP53 mutations (45.2%) localized to the L3 loop or LSH motif of the DNA-binding domain. TP53 disruptions had high co-occurrence with mutations in epigenetic regulators, spliceosome machinery, and cohesin complex and low co-occurrence with mutations in proliferative signaling genes. Ancestral and descendant TP53 mutations constituted measurable residual disease and fueled relapse. High mutant TP53 gene dosage predicted low durability of remission. The median overall survival (OS) was 280 days. Hypomethylating agent-based therapy served as an effective bridge to transplant, leading to improved median OS compared to patients who did not receive a transplant (14.7 vs. 5.1 months). OS was independent of the genomic location of TP53 disruption, which has implications for rational therapeutic design.

引用

页码：3348 / 3360

页数：13

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