Acute Lymphoblastic Leukemia with Myeloid Mutations Is a High-Risk Disease Associated with Clonal Hematopoiesis

被引：12

作者：

Saygin, Caner ^{[1
,10
]}

Zhang, Pu ^{[2
]}

Stauber, Jacob ^{[3
]}

Aldoss, Ibrahim ^{[4
]}

Sperling, Adam S. ^{[5
,6
]}

Weeks, Lachelle D. ^{[5
]}

Luskin, Marlise R. ^{[5
]}

Knepper, Todd C. ^{[7
]}

Wanjari, Pankhuri ^{[8
]}

Wang, Peng ^{[8
]}

Lager, Angela M. ^{[8
]}

Fitzpatrick, Carrie ^{[8
]}

Segal, Jeremy P. ^{[8
]}

Gharghabi, Mehdi ^{[2
]}

Gurbuxani, Sandeep ^{[8
]}

Venkataraman, Girish ^{[8
]}

Cheng, Jason X. ^{[8
]}

Eisfelder, Bart J. ^{[1
]}

Bohorquez, Oliver ^{[3
]}

Patel, Anand A. ^{[1
]}

Umesh Nagalakshmi, Sheethal ^{[9
]}

Jayaram, Savita ^{[9
]}

Odenike, Olatoyosi M. ^{[1
]}

Larson, Richard A. ^{[1
]}

Godley, Lucy A. ^{[1
]}

Arber, Daniel A. ^{[8
]}

Gibson, Christopher J. ^{[5
]}

Munshi, Nikhil C. ^{[5
]}

Marcucci, Guido ^{[4
]}

Ebert, Benjamin L. ^{[5
]}

Greally, John M. ^{[3
]}

Steidl, Ulrich ^{[3
]}

Lapalombella, Rosa ^{[2
]}

Shah, Bijal D. ^{[7
]}

Stock, Wendy ^{[1
]}

机构：

[1] Univ Chicago, Sect Hematol Oncol, Chicago, IL USA

[2] Ohio State Univ, Div Hematol, Columbus, OH USA

[3] Albert Einstein Coll Med Montefiore Hlth Syst, New York, NY USA

[4] Dept Hematol & Hematopoiet Cell Transplantat, City Hope, Duarte, CA USA

[5] Dana Farber Canc Inst, Boston, MA USA

[6] Brigham & Womens Hosp, Div Hematol, Boston, MA USA

[7] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA

[8] Univ Chicago, Dept Pathol, Chicago, IL USA

[9] MedGenome, San Francisco, CA USA

[10] Univ Chicago, Dept Med, Sect Hematol Oncol, 900 E 57th St,KCBD 7150,MC 2115, Chicago, IL 60637 USA

来源：

BLOOD CANCER DISCOVERY | 2024年 / 5卷 / 03期

关键词：

HEALTH-ORGANIZATION CLASSIFICATION; RESIDUAL DISEASE; B-CELL; THERAPY;

D O I：

10.1158/2643-3230.BCD-23-0106

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Myeloid neoplasms arise from preexisting clonal hematopoiesis (CH); however, the role of CH in the pathogenesis of acute lymphoblastic leukemia (ALL) is unknown. We found that 18% of adult ALL cases harbored TP53, and 16% had myeloid CH-associated gene mutations. ALL with myeloid mutations (MyM) had distinct genetic and clinical characteristics, associated with inferior survival. By using single-cell proteogenomic analysis, we demonstrated that myeloid mutations were present years before the diagnosis of ALL, and a subset of these clones expanded over time to manifest as dominant clones in ALL. Single-cell RNA sequencing revealed upregulation of genes associated with cell survival and resistance to apoptosis in B-ALL with MyM, which responds better to newer immunotherapeutic approaches. These findings define ALL with MyM as a high-risk disease that can arise from antecedent CH and offer new mechanistic insights to develop better therapeutic and preventative strategies.Significance: CH is a precursor lesion for lymphoblastic leukemogenesis. ALL with MyM has distinct genetic and clinical characteristics, associated with adverse survival outcomes after chemotherapy. CH can precede ALL years before diagnosis, and ALL with MyM is enriched with activated T cells that respond to immunotherapies such as blinatumomab. See related commentary by Iacobucci, p. 142.Significance: CH is a precursor lesion for lymphoblastic leukemogenesis. ALL with MyM has distinct genetic and clinical characteristics, associated with adverse survival outcomes after chemotherapy. CH can precede ALL years before diagnosis, and ALL with MyM is enriched with activated T cells that respond to immunotherapies such as blinatumomab. See related commentary by Iacobucci, p. 142.

引用

页码：164 / 179

页数：16

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