Multiomic profiling identifies predictors of survival in African American patients with acute myeloid leukemia

Andrew Stiff; Maarten Fornerod; Bailee N. Kain; Deedra Nicolet; Benjamin J. Kelly; Katherine E. Miller; Krzysztof Mrózek; Isaiah Boateng; Audrey Bollas; Elizabeth A.R. Garfinkle; Omolegho Momoh; Foluke A. Fasola; Hannah O. Olawumi; Nuria Mencia-Trinchant; Jean F. Kloppers; Anne Cecilia van Marle; Eileen Hu; Saranga Wijeratne; Gregory Wheeler; Christopher J. Walker; Jill Buss; Adrienne Heyrosa; Helee Desai; Andrea Laganson; Ethan Hamp; Yazan Abu-Shihab; Hasan Abaza; Parker Kronen; Sidharth Sen; Megan E. Johnstone; Kate Quinn; Ben Wronowski; Erin Hertlein; Linde A. Miles; Alice S. Mims; Christopher C. Oakes; James S. Blachly; Karilyn T. Larkin; Bethany Mundy-Bosse; Andrew J. Carroll; Bayard L. Powell; Jonathan E. Kolitz; Richard M. Stone; Cassandra Duarte; Diana Abbott; Maria L. Amaya; Craig T. Jordan; Geoffrey L. Uy; Wendy Stock; Kellie J. Archer; Electra D. Paskett; Monica L. Guzman; Ross L. Levine; Kamal Menghrajani; Debyani Chakravarty; Michael F. Berger; Daniel Bottomly; Shannon K. McWeeney; Jeffrey W. Tyner; John C. Byrd; Nathan Salomonis; H. Leighton Grimes; Elaine R. Mardis; Ann Kathrin Eisfeld

doi:10.1038/s41588-024-01929-x

Multiomic profiling identifies predictors of survival in African American patients with acute myeloid leukemia

Andrew Stiff, Maarten Fornerod, Bailee N. Kain, Deedra Nicolet, Benjamin J. Kelly, Katherine E. Miller, Krzysztof Mrózek, Isaiah Boateng, Audrey Bollas, Elizabeth A.R. Garfinkle, Omolegho Momoh, Foluke A. Fasola, Hannah O. Olawumi, Nuria Mencia-Trinchant, Jean F. Kloppers, Anne Cecilia van Marle, Eileen Hu, Saranga Wijeratne, Gregory Wheeler, Christopher J. WalkerJill Buss, Adrienne Heyrosa, Helee Desai, Andrea Laganson, Ethan Hamp, Yazan Abu-Shihab, Hasan Abaza, Parker Kronen, Sidharth Sen, Megan E. Johnstone, Kate Quinn, Ben Wronowski, Erin Hertlein, Linde A. Miles, Alice S. Mims, Christopher C. Oakes, James S. Blachly, Karilyn T. Larkin, Bethany Mundy-Bosse, Andrew J. Carroll, Bayard L. Powell, Jonathan E. Kolitz, Richard M. Stone, Cassandra Duarte, Diana Abbott, Maria L. Amaya, Craig T. Jordan, Geoffrey L. Uy, Wendy Stock, Kellie J. Archer, Electra D. Paskett, Monica L. Guzman, Ross L. Levine, Kamal Menghrajani, Debyani Chakravarty, Michael F. Berger, Daniel Bottomly, Shannon K. McWeeney, Jeffrey W. Tyner, John C. Byrd, Nathan Salomonis, H. Leighton Grimes, Elaine R. Mardis, Ann Kathrin Eisfeld

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Abstract

Genomic profiles and prognostic biomarkers in patients with acute myeloid leukemia (AML) from ancestry-diverse populations are underexplored. We analyzed the exomes and transcriptomes of 100 patients with AML with genomically confirmed African ancestry (Black; Alliance) and compared their somatic mutation frequencies with those of 323 self-reported white patients with AML, 55% of whom had genomically confirmed European ancestry (white; BeatAML). Here we find that 73% of 162 gene mutations recurrent in Black patients, including a hitherto unreported PHIP alteration detected in 7% of patients, were found in one white patient or not detected. Black patients with myelodysplasia-related AML were younger than white patients suggesting intrinsic and/or extrinsic dysplasia-causing stressors. On multivariable analyses of Black patients, NPM1 and NRAS mutations were associated with inferior disease-free and IDH1 and IDH2 mutations with reduced overall survival. Inflammatory profiles, cell type distributions and transcriptional profiles differed between Black and white patients with NPM1 mutations. Incorporation of ancestry-specific risk markers into the 2022 European LeukemiaNet genetic risk stratification changed risk group assignment for one-third of Black patients and improved their outcome prediction.

Original language	English (US)
Pages (from-to)	2434-2446
Number of pages	13
Journal	Nature genetics
Volume	56
Issue number	11
DOIs	https://doi.org/10.1038/s41588-024-01929-x
State	Published - Nov 2024

ASJC Scopus subject areas

Genetics

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Stiff, A., Fornerod, M., Kain, B. N., Nicolet, D., Kelly, B. J., Miller, K. E., Mrózek, K., Boateng, I., Bollas, A., Garfinkle, E. A. R., Momoh, O., Fasola, F. A., Olawumi, H. O., Mencia-Trinchant, N., Kloppers, J. F., van Marle, A. C., Hu, E., Wijeratne, S., Wheeler, G., ... Eisfeld, A. K. (2024). Multiomic profiling identifies predictors of survival in African American patients with acute myeloid leukemia. Nature genetics, 56(11), 2434-2446. https://doi.org/10.1038/s41588-024-01929-x

Stiff, A, Fornerod, M, Kain, BN, Nicolet, D, Kelly, BJ, Miller, KE, Mrózek, K, Boateng, I, Bollas, A, Garfinkle, EAR, Momoh, O, Fasola, FA, Olawumi, HO, Mencia-Trinchant, N, Kloppers, JF, van Marle, AC, Hu, E, Wijeratne, S, Wheeler, G, Walker, CJ, Buss, J, Heyrosa, A, Desai, H, Laganson, A, Hamp, E, Abu-Shihab, Y, Abaza, H, Kronen, P, Sen, S, Johnstone, ME, Quinn, K, Wronowski, B, Hertlein, E, Miles, LA, Mims, AS, Oakes, CC, Blachly, JS, Larkin, KT, Mundy-Bosse, B, Carroll, AJ, Powell, BL, Kolitz, JE, Stone, RM, Duarte, C, Abbott, D, Amaya, ML, Jordan, CT, Uy, GL, Stock, W, Archer, KJ, Paskett, ED, Guzman, ML, Levine, RL, Menghrajani, K, Chakravarty, D, Berger, MF, Bottomly, D, McWeeney, SK , Tyner, JW, Byrd, JC, Salomonis, N, Grimes, HL, Mardis, ER & Eisfeld, AK 2024, 'Multiomic profiling identifies predictors of survival in African American patients with acute myeloid leukemia', Nature genetics, vol. 56, no. 11, pp. 2434-2446. https://doi.org/10.1038/s41588-024-01929-x

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title = "Multiomic profiling identifies predictors of survival in African American patients with acute myeloid leukemia",

abstract = "Genomic profiles and prognostic biomarkers in patients with acute myeloid leukemia (AML) from ancestry-diverse populations are underexplored. We analyzed the exomes and transcriptomes of 100 patients with AML with genomically confirmed African ancestry (Black; Alliance) and compared their somatic mutation frequencies with those of 323 self-reported white patients with AML, 55% of whom had genomically confirmed European ancestry (white; BeatAML). Here we find that 73% of 162 gene mutations recurrent in Black patients, including a hitherto unreported PHIP alteration detected in 7% of patients, were found in one white patient or not detected. Black patients with myelodysplasia-related AML were younger than white patients suggesting intrinsic and/or extrinsic dysplasia-causing stressors. On multivariable analyses of Black patients, NPM1 and NRAS mutations were associated with inferior disease-free and IDH1 and IDH2 mutations with reduced overall survival. Inflammatory profiles, cell type distributions and transcriptional profiles differed between Black and white patients with NPM1 mutations. Incorporation of ancestry-specific risk markers into the 2022 European LeukemiaNet genetic risk stratification changed risk group assignment for one-third of Black patients and improved their outcome prediction.",

author = "Andrew Stiff and Maarten Fornerod and Kain, {Bailee N.} and Deedra Nicolet and Kelly, {Benjamin J.} and Miller, {Katherine E.} and Krzysztof Mr{\'o}zek and Isaiah Boateng and Audrey Bollas and Garfinkle, {Elizabeth A.R.} and Omolegho Momoh and Fasola, {Foluke A.} and Olawumi, {Hannah O.} and Nuria Mencia-Trinchant and Kloppers, {Jean F.} and {van Marle}, {Anne Cecilia} and Eileen Hu and Saranga Wijeratne and Gregory Wheeler and Walker, {Christopher J.} and Jill Buss and Adrienne Heyrosa and Helee Desai and Andrea Laganson and Ethan Hamp and Yazan Abu-Shihab and Hasan Abaza and Parker Kronen and Sidharth Sen and Johnstone, {Megan E.} and Kate Quinn and Ben Wronowski and Erin Hertlein and Miles, {Linde A.} and Mims, {Alice S.} and Oakes, {Christopher C.} and Blachly, {James S.} and Larkin, {Karilyn T.} and Bethany Mundy-Bosse and Carroll, {Andrew J.} and Powell, {Bayard L.} and Kolitz, {Jonathan E.} and Stone, {Richard M.} and Cassandra Duarte and Diana Abbott and Amaya, {Maria L.} and Jordan, {Craig T.} and Uy, {Geoffrey L.} and Wendy Stock and Archer, {Kellie J.} and Paskett, {Electra D.} and Guzman, {Monica L.} and Levine, {Ross L.} and Kamal Menghrajani and Debyani Chakravarty and Berger, {Michael F.} and Daniel Bottomly and McWeeney, {Shannon K.} and Tyner, {Jeffrey W.} and Byrd, {John C.} and Nathan Salomonis and Grimes, {H. Leighton} and Mardis, {Elaine R.} and Eisfeld, {Ann Kathrin}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = nov,

doi = "10.1038/s41588-024-01929-x",

language = "English (US)",

volume = "56",

pages = "2434--2446",

journal = "Nature genetics",

issn = "1061-4036",

publisher = "Nature Research",

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TY - JOUR

T1 - Multiomic profiling identifies predictors of survival in African American patients with acute myeloid leukemia

AU - Stiff, Andrew

AU - Fornerod, Maarten

AU - Kain, Bailee N.

AU - Nicolet, Deedra

AU - Kelly, Benjamin J.

AU - Miller, Katherine E.

AU - Mrózek, Krzysztof

AU - Boateng, Isaiah

AU - Bollas, Audrey

AU - Garfinkle, Elizabeth A.R.

AU - Momoh, Omolegho

AU - Fasola, Foluke A.

AU - Olawumi, Hannah O.

AU - Mencia-Trinchant, Nuria

AU - Kloppers, Jean F.

AU - van Marle, Anne Cecilia

AU - Hu, Eileen

AU - Wijeratne, Saranga

AU - Wheeler, Gregory

AU - Walker, Christopher J.

AU - Buss, Jill

AU - Heyrosa, Adrienne

AU - Desai, Helee

AU - Laganson, Andrea

AU - Hamp, Ethan

AU - Abu-Shihab, Yazan

AU - Abaza, Hasan

AU - Kronen, Parker

AU - Sen, Sidharth

AU - Johnstone, Megan E.

AU - Quinn, Kate

AU - Wronowski, Ben

AU - Hertlein, Erin

AU - Miles, Linde A.

AU - Mims, Alice S.

AU - Oakes, Christopher C.

AU - Blachly, James S.

AU - Larkin, Karilyn T.

AU - Mundy-Bosse, Bethany

AU - Carroll, Andrew J.

AU - Powell, Bayard L.

AU - Kolitz, Jonathan E.

AU - Stone, Richard M.

AU - Duarte, Cassandra

AU - Abbott, Diana

AU - Amaya, Maria L.

AU - Jordan, Craig T.

AU - Uy, Geoffrey L.

AU - Stock, Wendy

AU - Archer, Kellie J.

AU - Paskett, Electra D.

AU - Guzman, Monica L.

AU - Levine, Ross L.

AU - Menghrajani, Kamal

AU - Chakravarty, Debyani

AU - Berger, Michael F.

AU - Bottomly, Daniel

AU - McWeeney, Shannon K.

AU - Tyner, Jeffrey W.

AU - Byrd, John C.

AU - Salomonis, Nathan

AU - Grimes, H. Leighton

AU - Mardis, Elaine R.

AU - Eisfeld, Ann Kathrin

PY - 2024/11

Y1 - 2024/11

N2 - Genomic profiles and prognostic biomarkers in patients with acute myeloid leukemia (AML) from ancestry-diverse populations are underexplored. We analyzed the exomes and transcriptomes of 100 patients with AML with genomically confirmed African ancestry (Black; Alliance) and compared their somatic mutation frequencies with those of 323 self-reported white patients with AML, 55% of whom had genomically confirmed European ancestry (white; BeatAML). Here we find that 73% of 162 gene mutations recurrent in Black patients, including a hitherto unreported PHIP alteration detected in 7% of patients, were found in one white patient or not detected. Black patients with myelodysplasia-related AML were younger than white patients suggesting intrinsic and/or extrinsic dysplasia-causing stressors. On multivariable analyses of Black patients, NPM1 and NRAS mutations were associated with inferior disease-free and IDH1 and IDH2 mutations with reduced overall survival. Inflammatory profiles, cell type distributions and transcriptional profiles differed between Black and white patients with NPM1 mutations. Incorporation of ancestry-specific risk markers into the 2022 European LeukemiaNet genetic risk stratification changed risk group assignment for one-third of Black patients and improved their outcome prediction.

AB - Genomic profiles and prognostic biomarkers in patients with acute myeloid leukemia (AML) from ancestry-diverse populations are underexplored. We analyzed the exomes and transcriptomes of 100 patients with AML with genomically confirmed African ancestry (Black; Alliance) and compared their somatic mutation frequencies with those of 323 self-reported white patients with AML, 55% of whom had genomically confirmed European ancestry (white; BeatAML). Here we find that 73% of 162 gene mutations recurrent in Black patients, including a hitherto unreported PHIP alteration detected in 7% of patients, were found in one white patient or not detected. Black patients with myelodysplasia-related AML were younger than white patients suggesting intrinsic and/or extrinsic dysplasia-causing stressors. On multivariable analyses of Black patients, NPM1 and NRAS mutations were associated with inferior disease-free and IDH1 and IDH2 mutations with reduced overall survival. Inflammatory profiles, cell type distributions and transcriptional profiles differed between Black and white patients with NPM1 mutations. Incorporation of ancestry-specific risk markers into the 2022 European LeukemiaNet genetic risk stratification changed risk group assignment for one-third of Black patients and improved their outcome prediction.

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U2 - 10.1038/s41588-024-01929-x

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JO - Nature genetics

JF - Nature genetics

IS - 11

ER -

Multiomic profiling identifies predictors of survival in African American patients with acute myeloid leukemia

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