Acute Lymphoblastic Leukemia with Myeloid Mutations Is a High-Risk Disease Associated with Clonal Hematopoiesis
©2023 The Authors; Published by the American Association for Cancer Research..
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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:5 |
|---|---|
| Enthalten in: |
Blood cancer discovery - 5(2024), 3 vom: 01. Mai, Seite 164-179 |
| Sprache: |
Englisch |
|---|
| Links: |
|---|
| Themen: |
Journal Article |
|---|
| Anmerkungen: |
Date Completed 01.05.2024 Date Revised 03.05.2024 published: Print Citation Status MEDLINE |
|---|
| doi: |
10.1158/2643-3230.BCD-23-0106 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM366408372 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM366408372 | ||
| 003 | DE-627 | ||
| 005 | 20240503232219.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231229s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1158/2643-3230.BCD-23-0106 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1396.xml |
| 035 | |a (DE-627)NLM366408372 | ||
| 035 | |a (NLM)38150184 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Saygin, Caner |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Acute Lymphoblastic Leukemia with Myeloid Mutations Is a High-Risk Disease Associated with Clonal Hematopoiesis |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 01.05.2024 | ||
| 500 | |a Date Revised 03.05.2024 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a ©2023 The Authors; Published by the American Association for Cancer Research. | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 700 | 1 | |a Zhang, Pu |e verfasserin |4 aut | |
| 700 | 1 | |a Stauber, Jacob |e verfasserin |4 aut | |
| 700 | 1 | |a Aldoss, Ibrahim |e verfasserin |4 aut | |
| 700 | 1 | |a Sperling, Adam S |e verfasserin |4 aut | |
| 700 | 1 | |a Weeks, Lachelle D |e verfasserin |4 aut | |
| 700 | 1 | |a Luskin, Marlise R |e verfasserin |4 aut | |
| 700 | 1 | |a Knepper, Todd C |e verfasserin |4 aut | |
| 700 | 1 | |a Wanjari, Pankhuri |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Peng |e verfasserin |4 aut | |
| 700 | 1 | |a Lager, Angela M |e verfasserin |4 aut | |
| 700 | 1 | |a Fitzpatrick, Carrie |e verfasserin |4 aut | |
| 700 | 1 | |a Segal, Jeremy P |e verfasserin |4 aut | |
| 700 | 1 | |a Gharghabi, Mehdi |e verfasserin |4 aut | |
| 700 | 1 | |a Gurbuxani, Sandeep |e verfasserin |4 aut | |
| 700 | 1 | |a Venkataraman, Girish |e verfasserin |4 aut | |
| 700 | 1 | |a Cheng, Jason X |e verfasserin |4 aut | |
| 700 | 1 | |a Eisfelder, Bart J |e verfasserin |4 aut | |
| 700 | 1 | |a Bohorquez, Oliver |e verfasserin |4 aut | |
| 700 | 1 | |a Patel, Anand A |e verfasserin |4 aut | |
| 700 | 1 | |a Umesh Nagalakshmi, Sheethal |e verfasserin |4 aut | |
| 700 | 1 | |a Jayaram, Savita |e verfasserin |4 aut | |
| 700 | 1 | |a Odenike, Olatoyosi M |e verfasserin |4 aut | |
| 700 | 1 | |a Larson, Richard A |e verfasserin |4 aut | |
| 700 | 1 | |a Godley, Lucy A |e verfasserin |4 aut | |
| 700 | 1 | |a Arber, Daniel A |e verfasserin |4 aut | |
| 700 | 1 | |a Gibson, Christopher J |e verfasserin |4 aut | |
| 700 | 1 | |a Munshi, Nikhil C |e verfasserin |4 aut | |
| 700 | 1 | |a Marcucci, Guido |e verfasserin |4 aut | |
| 700 | 1 | |a Ebert, Benjamin L |e verfasserin |4 aut | |
| 700 | 1 | |a Greally, John M |e verfasserin |4 aut | |
| 700 | 1 | |a Steidl, Ulrich |e verfasserin |4 aut | |
| 700 | 1 | |a Lapalombella, Rosa |e verfasserin |4 aut | |
| 700 | 1 | |a Shah, Bijal D |e verfasserin |4 aut | |
| 700 | 1 | |a Stock, Wendy |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Blood cancer discovery |d 2020 |g 5(2024), 3 vom: 01. Mai, Seite 164-179 |w (DE-627)NLM31368555X |x 2643-3249 |7 nnns |
| 773 | 1 | 8 | |g volume:5 |g year:2024 |g number:3 |g day:01 |g month:05 |g pages:164-179 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1158/2643-3230.BCD-23-0106 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 5 |j 2024 |e 3 |b 01 |c 05 |h 164-179 | ||