Integrative genomic analysis of adult mixed phenotype acute leukemia delineates lineage associated molecular subtypes

Koichi Takahashi; Feng Wang; Kiyomi Morita; Yuanqing Yan; Peter Hu; Pei Zhao; Abdallah Abou Zhar; Chang Jiun Wu; Curtis Gumbs; Latasha Little; Samantha Tippen; Rebecca Thornton; Marcus Coyle; Marisela Mendoza; Erika Thompson; Jianhua Zhang; Courtney D. Dinardo; Nitin Jain; Farhad Ravandi; Jorge E. Cortes; Guillermo Garcia-Manero; Steven Kornblau; Michael Andreeff; Elias Jabbour; Carlos Bueso-Ramos; Akifumi Takaori-Kondo; Marina Konopleva; Keyur Patel; Hagop Kantarjian; P. Andrew Futreal

doi:10.1038/s41467-018-04924-z

Integrative genomic analysis of adult mixed phenotype acute leukemia delineates lineage associated molecular subtypes

Koichi Takahashi, Feng Wang, Kiyomi Morita, Yuanqing Yan, Peter Hu, Pei Zhao, Abdallah Abou Zhar, Chang Jiun Wu, Curtis Gumbs, Latasha Little, Samantha Tippen, Rebecca Thornton, Marcus Coyle, Marisela Mendoza, Erika Thompson, Jianhua Zhang, Courtney D. Dinardo, Nitin Jain, Farhad Ravandi, Jorge E. CortesGuillermo Garcia-Manero, Steven Kornblau, Michael Andreeff, Elias Jabbour, Carlos Bueso-Ramos, Akifumi Takaori-Kondo, Marina Konopleva, Keyur Patel, Hagop Kantarjian, P. Andrew Futreal

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Abstract

Mixed phenotype acute leukemia (MPAL) is a rare subtype of acute leukemia characterized by leukemic blasts presenting myeloid and lymphoid markers. Here we report data from integrated genomic analysis on 31 MPAL samples and compare molecular profiling with that from acute myeloid leukemia (AML), B cell acute lymphoblastic leukemia (B-ALL), and T cell acute lymphoblastic leukemia (T-ALL). Consistent with the mixed immunophenotype, both AML-type and ALL-type mutations are detected in MPAL. Myeloid-B and myeloid-T MPAL show distinct mutation and methylation signatures that are associated with differences in lineage-commitment gene expressions. Genome-wide methylation comparison among MPAL, AML, B-ALL, and T-ALL sub-classifies MPAL into AML-type and ALL-type MPAL, which is associated with better clinical response when lineage-matched therapy is given. These results elucidate the genetic and epigenetic heterogeneity of MPAL and its genetic distinction from AML, B-ALL, and T-ALL and further provide proof of concept for a molecularly guided precision therapy approach in MPAL.

Original language	English (US)
Article number	2670
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-04924-z
State	Published - Dec 1 2018
Externally published	Yes

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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Takahashi, K., Wang, F., Morita, K., Yan, Y., Hu, P., Zhao, P., Zhar, A. A., Wu, C. J., Gumbs, C., Little, L., Tippen, S., Thornton, R., Coyle, M., Mendoza, M., Thompson, E., Zhang, J., Dinardo, C. D., Jain, N., Ravandi, F., ... Futreal, P. A. (2018). Integrative genomic analysis of adult mixed phenotype acute leukemia delineates lineage associated molecular subtypes. Nature communications, 9(1), Article 2670. https://doi.org/10.1038/s41467-018-04924-z

Takahashi, K, Wang, F, Morita, K, Yan, Y, Hu, P, Zhao, P, Zhar, AA, Wu, CJ, Gumbs, C, Little, L, Tippen, S, Thornton, R, Coyle, M, Mendoza, M, Thompson, E, Zhang, J, Dinardo, CD, Jain, N, Ravandi, F, Cortes, JE, Garcia-Manero, G, Kornblau, S, Andreeff, M, Jabbour, E, Bueso-Ramos, C, Takaori-Kondo, A, Konopleva, M, Patel, K, Kantarjian, H & Futreal, PA 2018, 'Integrative genomic analysis of adult mixed phenotype acute leukemia delineates lineage associated molecular subtypes', Nature communications, vol. 9, no. 1, 2670. https://doi.org/10.1038/s41467-018-04924-z

@article{0b682ab8d5654e98b6110ca973ca93db,

title = "Integrative genomic analysis of adult mixed phenotype acute leukemia delineates lineage associated molecular subtypes",

abstract = "Mixed phenotype acute leukemia (MPAL) is a rare subtype of acute leukemia characterized by leukemic blasts presenting myeloid and lymphoid markers. Here we report data from integrated genomic analysis on 31 MPAL samples and compare molecular profiling with that from acute myeloid leukemia (AML), B cell acute lymphoblastic leukemia (B-ALL), and T cell acute lymphoblastic leukemia (T-ALL). Consistent with the mixed immunophenotype, both AML-type and ALL-type mutations are detected in MPAL. Myeloid-B and myeloid-T MPAL show distinct mutation and methylation signatures that are associated with differences in lineage-commitment gene expressions. Genome-wide methylation comparison among MPAL, AML, B-ALL, and T-ALL sub-classifies MPAL into AML-type and ALL-type MPAL, which is associated with better clinical response when lineage-matched therapy is given. These results elucidate the genetic and epigenetic heterogeneity of MPAL and its genetic distinction from AML, B-ALL, and T-ALL and further provide proof of concept for a molecularly guided precision therapy approach in MPAL.",

author = "Koichi Takahashi and Feng Wang and Kiyomi Morita and Yuanqing Yan and Peter Hu and Pei Zhao and Zhar, {Abdallah Abou} and Wu, {Chang Jiun} and Curtis Gumbs and Latasha Little and Samantha Tippen and Rebecca Thornton and Marcus Coyle and Marisela Mendoza and Erika Thompson and Jianhua Zhang and Dinardo, {Courtney D.} and Nitin Jain and Farhad Ravandi and Cortes, {Jorge E.} and Guillermo Garcia-Manero and Steven Kornblau and Michael Andreeff and Elias Jabbour and Carlos Bueso-Ramos and Akifumi Takaori-Kondo and Marina Konopleva and Keyur Patel and Hagop Kantarjian and Futreal, {P. Andrew}",

note = "Funding Information: This study was supported in part by the Cancer Prevention Research Institute of Texas (grant R120501 to P.A.F.), the Welch Foundation (grant G-0040 to P.A.F.), the UT System STARS Award (grant PS100149 to P.A.F.), the Red and Charline McCombs Institute for the Early Detection and Treatment of Cancer Award (to K.T.), an Institutional Research Grant at the MD Anderson Cancer Center (to K.T.), Khalifa Scholar Award (to K.T.), Charif Souki Cancer Research Fund (to H.K.), MD Anderson Cancer Center Leukemia SPORE P50 CA100632 (to H.K.), MD Anderson Cancer Center Support Grant (NIH P30 CA016672), and by generous philanthropic contributions to MD Anderson{\textquoteright}s Moon Shot Program (P.A.F.). We thank Kathryn Hale at Department Scientific Publications at MD Anderson for providing scientific editing of the manuscript. Publisher Copyright: {\textcopyright} 2018 The Author(s).",

year = "2018",

month = dec,

day = "1",

doi = "10.1038/s41467-018-04924-z",

language = "English (US)",

volume = "9",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

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TY - JOUR

T1 - Integrative genomic analysis of adult mixed phenotype acute leukemia delineates lineage associated molecular subtypes

AU - Takahashi, Koichi

AU - Wang, Feng

AU - Morita, Kiyomi

AU - Yan, Yuanqing

AU - Hu, Peter

AU - Zhao, Pei

AU - Zhar, Abdallah Abou

AU - Wu, Chang Jiun

AU - Gumbs, Curtis

AU - Little, Latasha

AU - Tippen, Samantha

AU - Thornton, Rebecca

AU - Coyle, Marcus

AU - Mendoza, Marisela

AU - Thompson, Erika

AU - Zhang, Jianhua

AU - Dinardo, Courtney D.

AU - Jain, Nitin

AU - Ravandi, Farhad

AU - Cortes, Jorge E.

AU - Garcia-Manero, Guillermo

AU - Kornblau, Steven

AU - Andreeff, Michael

AU - Jabbour, Elias

AU - Bueso-Ramos, Carlos

AU - Takaori-Kondo, Akifumi

AU - Konopleva, Marina

AU - Patel, Keyur

AU - Kantarjian, Hagop

AU - Futreal, P. Andrew

N1 - Funding Information: This study was supported in part by the Cancer Prevention Research Institute of Texas (grant R120501 to P.A.F.), the Welch Foundation (grant G-0040 to P.A.F.), the UT System STARS Award (grant PS100149 to P.A.F.), the Red and Charline McCombs Institute for the Early Detection and Treatment of Cancer Award (to K.T.), an Institutional Research Grant at the MD Anderson Cancer Center (to K.T.), Khalifa Scholar Award (to K.T.), Charif Souki Cancer Research Fund (to H.K.), MD Anderson Cancer Center Leukemia SPORE P50 CA100632 (to H.K.), MD Anderson Cancer Center Support Grant (NIH P30 CA016672), and by generous philanthropic contributions to MD Anderson’s Moon Shot Program (P.A.F.). We thank Kathryn Hale at Department Scientific Publications at MD Anderson for providing scientific editing of the manuscript. Publisher Copyright: © 2018 The Author(s).

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Mixed phenotype acute leukemia (MPAL) is a rare subtype of acute leukemia characterized by leukemic blasts presenting myeloid and lymphoid markers. Here we report data from integrated genomic analysis on 31 MPAL samples and compare molecular profiling with that from acute myeloid leukemia (AML), B cell acute lymphoblastic leukemia (B-ALL), and T cell acute lymphoblastic leukemia (T-ALL). Consistent with the mixed immunophenotype, both AML-type and ALL-type mutations are detected in MPAL. Myeloid-B and myeloid-T MPAL show distinct mutation and methylation signatures that are associated with differences in lineage-commitment gene expressions. Genome-wide methylation comparison among MPAL, AML, B-ALL, and T-ALL sub-classifies MPAL into AML-type and ALL-type MPAL, which is associated with better clinical response when lineage-matched therapy is given. These results elucidate the genetic and epigenetic heterogeneity of MPAL and its genetic distinction from AML, B-ALL, and T-ALL and further provide proof of concept for a molecularly guided precision therapy approach in MPAL.

AB - Mixed phenotype acute leukemia (MPAL) is a rare subtype of acute leukemia characterized by leukemic blasts presenting myeloid and lymphoid markers. Here we report data from integrated genomic analysis on 31 MPAL samples and compare molecular profiling with that from acute myeloid leukemia (AML), B cell acute lymphoblastic leukemia (B-ALL), and T cell acute lymphoblastic leukemia (T-ALL). Consistent with the mixed immunophenotype, both AML-type and ALL-type mutations are detected in MPAL. Myeloid-B and myeloid-T MPAL show distinct mutation and methylation signatures that are associated with differences in lineage-commitment gene expressions. Genome-wide methylation comparison among MPAL, AML, B-ALL, and T-ALL sub-classifies MPAL into AML-type and ALL-type MPAL, which is associated with better clinical response when lineage-matched therapy is given. These results elucidate the genetic and epigenetic heterogeneity of MPAL and its genetic distinction from AML, B-ALL, and T-ALL and further provide proof of concept for a molecularly guided precision therapy approach in MPAL.

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U2 - 10.1038/s41467-018-04924-z

DO - 10.1038/s41467-018-04924-z

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SN - 2041-1723

VL - 9

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 2670

ER -

Integrative genomic analysis of adult mixed phenotype acute leukemia delineates lineage associated molecular subtypes

Abstract

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