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

Caner Saygin; Pu Zhang; Jacob Stauber; Ibrahim Aldoss; Adam S. Sperling; Lachelle D. Weeks; Marlise R. Luskin; Todd C. Knepper; Pankhuri Wanjari; Peng Wang; Angela M. Lager; Carrie Fitzpatrick; Jeremy P. Segal; Mehdi Gharghabi; Sandeep Gurbuxani; Girish Venkataraman; Jason X. Cheng; Bart J. Eisfelder; Oliver Bohorquez; Anand A. Patel; Sheethal Umesh Nagalakshmi; Savita Jayaram; Olatoyosi M. Odenike; Richard A. Larson; Lucy A. Godley; Daniel A. Arber; Christopher J. Gibson; Nikhil C. Munshi; Guido Marcucci; Benjamin L. Ebert; John M. Greally; Ulrich Steidl; Rosa Lapalombella; Bijal D. Shah; Wendy Stock

doi:10.1158/2643-3230.BCD-23-0106

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

Caner Saygin^*, Pu Zhang, Jacob Stauber, Ibrahim Aldoss, Adam S. Sperling, Lachelle D. Weeks, Marlise R. Luskin, Todd C. Knepper, Pankhuri Wanjari, Peng Wang, Angela M. Lager, Carrie Fitzpatrick, Jeremy P. Segal, Mehdi Gharghabi, Sandeep Gurbuxani, Girish Venkataraman, Jason X. Cheng, Bart J. Eisfelder, Oliver Bohorquez, Anand A. PatelSheethal Umesh Nagalakshmi, Savita Jayaram, Olatoyosi M. Odenike, Richard A. Larson, Lucy A. Godley, Daniel A. Arber, Christopher J. Gibson, Nikhil C. Munshi, Guido Marcucci, Benjamin L. Ebert, John M. Greally, Ulrich Steidl, Rosa Lapalombella, Bijal D. Shah, Wendy Stock

^*Corresponding author for this work

Medicine, Hematology Oncology Division

Research output: Contribution to journal › Article › peer-review

10 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	164-179
Number of pages	16
Journal	Blood cancer discovery
Volume	5
Issue number	3
DOIs	https://doi.org/10.1158/2643-3230.BCD-23-0106
State	Published - May 1 2024

Funding

C. Saygin is supported by the Leukemia Lymphoma Society Special Fellow Award, Prevent Cancer Foundation Fellowship, and Cancer Research Foundation. This work was supported by NIH (R01HL082945, P01CA066996, and P50CA206963), the Howard Hughes Medical Institute, the Edward P. Evans Foundation, and the Leukemia and Lymphoma Society (to B.L. Ebert). A.S. Sperling was supported by grants from the National Cancer Institute (K08CA252174) and the U.S. Department of Defense (CA210827). The authors thank Dr. Ross Levine for the kind gift of Tet2fl/flVav-Cre mice, Dr. Pieter Faber and Ms. Sandy Arun from Genomics Core for their assistance with single-cell studies, and Janice Pacheco and Clinton Osei of the University of Chicago for their assistance with patient samples. C. Saygin reports grants from the Leukemia Lymphoma Society, Prevent Cancer Foundation, and Cancer Research Foundation during the conduct of the study. J. Stauber reports grants from National Heart, Lung, and Blood Institute during the conduct of the study. A.S. Sperling reports personal fees from Novartis and Roche outside the submitted work. L.D. Weeks reports grants from the American Society of Hematology and Edward P. Evans Foundation for MDS during the conduct of the study and personal fees from Vertex, Sobi, and AbbVie outside the submitted work. M.R. Luskin reports

ASJC Scopus subject areas

General Medicine

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10.1158/2643-3230.BCD-23-0106

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Saygin, C., Zhang, P., Stauber, J., Aldoss, I., Sperling, A. S., Weeks, L. D., Luskin, M. R., Knepper, T. C., Wanjari, P., Wang, P., Lager, A. M., Fitzpatrick, C., Segal, J. P., Gharghabi, M., Gurbuxani, S., Venkataraman, G., Cheng, J. X., Eisfelder, B. J., Bohorquez, O., ... Stock, W. (2024). Acute Lymphoblastic Leukemia with Myeloid Mutations Is a High-Risk Disease Associated with Clonal Hematopoiesis. Blood cancer discovery, 5(3), 164-179. https://doi.org/10.1158/2643-3230.BCD-23-0106

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title = "Acute Lymphoblastic Leukemia with Myeloid Mutations Is a High-Risk Disease Associated with Clonal Hematopoiesis",

abstract = "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.",

author = "Caner Saygin and Pu Zhang and Jacob Stauber and Ibrahim Aldoss and Sperling, {Adam S.} and Weeks, {Lachelle D.} and Luskin, {Marlise R.} and Knepper, {Todd C.} and Pankhuri Wanjari and Peng Wang and Lager, {Angela M.} and Carrie Fitzpatrick and Segal, {Jeremy P.} and Mehdi Gharghabi and Sandeep Gurbuxani and Girish Venkataraman and Cheng, {Jason X.} and Eisfelder, {Bart J.} and Oliver Bohorquez and Patel, {Anand A.} and Nagalakshmi, {Sheethal Umesh} and Savita Jayaram and Odenike, {Olatoyosi M.} and Larson, {Richard A.} and Godley, {Lucy A.} and Arber, {Daniel A.} and Gibson, {Christopher J.} and Munshi, {Nikhil C.} and Guido Marcucci and Ebert, {Benjamin L.} and Greally, {John M.} and Ulrich Steidl and Rosa Lapalombella and Shah, {Bijal D.} and Wendy Stock",

note = "Publisher Copyright: {\textcopyright}2023The Authors; Published by the American Association for Cancer Research.",

year = "2024",

month = may,

day = "1",

doi = "10.1158/2643-3230.BCD-23-0106",

language = "English (US)",

volume = "5",

pages = "164--179",

journal = "Blood cancer discovery",

issn = "2643-3230",

publisher = "NLM (Medline)",

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Saygin, C, Zhang, P, Stauber, J, Aldoss, I, Sperling, AS, Weeks, LD, Luskin, MR, Knepper, TC, Wanjari, P, Wang, P, Lager, AM, Fitzpatrick, C, Segal, JP, Gharghabi, M, Gurbuxani, S, Venkataraman, G, Cheng, JX, Eisfelder, BJ, Bohorquez, O, Patel, AA, Nagalakshmi, SU, Jayaram, S, Odenike, OM, Larson, RA, Godley, LA, Arber, DA, Gibson, CJ, Munshi, NC, Marcucci, G, Ebert, BL, Greally, JM, Steidl, U, Lapalombella, R, Shah, BD & Stock, W 2024, 'Acute Lymphoblastic Leukemia with Myeloid Mutations Is a High-Risk Disease Associated with Clonal Hematopoiesis', Blood cancer discovery, vol. 5, no. 3, pp. 164-179. https://doi.org/10.1158/2643-3230.BCD-23-0106

TY - JOUR

T1 - Acute Lymphoblastic Leukemia with Myeloid Mutations Is a High-Risk Disease Associated with Clonal Hematopoiesis

AU - Saygin, Caner

AU - Zhang, Pu

AU - Stauber, Jacob

AU - Aldoss, Ibrahim

AU - Sperling, Adam S.

AU - Weeks, Lachelle D.

AU - Luskin, Marlise R.

AU - Knepper, Todd C.

AU - Wanjari, Pankhuri

AU - Wang, Peng

AU - Lager, Angela M.

AU - Fitzpatrick, Carrie

AU - Segal, Jeremy P.

AU - Gharghabi, Mehdi

AU - Gurbuxani, Sandeep

AU - Venkataraman, Girish

AU - Cheng, Jason X.

AU - Eisfelder, Bart J.

AU - Bohorquez, Oliver

AU - Patel, Anand A.

AU - Nagalakshmi, Sheethal Umesh

AU - Jayaram, Savita

AU - Odenike, Olatoyosi M.

AU - Larson, Richard A.

AU - Godley, Lucy A.

AU - Arber, Daniel A.

AU - Gibson, Christopher J.

AU - Munshi, Nikhil C.

AU - Marcucci, Guido

AU - Ebert, Benjamin L.

AU - Greally, John M.

AU - Steidl, Ulrich

AU - Lapalombella, Rosa

AU - Shah, Bijal D.

AU - Stock, Wendy

PY - 2024/5/1

Y1 - 2024/5/1

N2 - 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.

AB - 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.

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U2 - 10.1158/2643-3230.BCD-23-0106

DO - 10.1158/2643-3230.BCD-23-0106

M3 - Article

C2 - 38150184

AN - SCOPUS:85192027992

SN - 2643-3230

VL - 5

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JO - Blood cancer discovery

JF - Blood cancer discovery

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ER -

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

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