Genomic subtyping and therapeutic targeting of acute erythroleukemia

Ilaria Iacobucci, Ji Wen, Manja Meggendorfer, John K. Choi, Lei Shi, Stanley B. Pounds, Catherine L. Carmichael, Katherine E. Masih, Sarah M. Morris, R. Coleman Lindsley, Laura J. Janke, Thomas B. Alexander, Guangchun Song, Chunxu Qu, Yongjin Li, Debbie Payne-Turner, Daisuke Tomizawa, Nobutaka Kiyokawa, Marcus Valentine, Virginia Valentine & 28 others Giuseppe Basso, Franco Locatelli, Eric J. Enemark, Shirley K.Y. Kham, Allen E.J. Yeoh, Xiaotu Ma, Xin Zhou, Edgar Sioson, Michael Rusch, Rhonda E. Ries, Elliot Stieglitz, Stephen P. Hunger, Andrew H. Wei, L. Bik To, Ian D. Lewis, Richard J. D’Andrea, Benjamin T. Kile, Anna L. Brown, Hamish S. Scott, Christopher N. Hahn, Paula Marlton, Deqing Pei, Cheng Cheng, Mignon L. Loh, Benjamin L. Ebert, Soheil Meshinchi, Torsten Haferlach, Charles G. Mullighan

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Acute erythroid leukemia (AEL) is a high-risk leukemia of poorly understood genetic basis, with controversy regarding diagnosis in the spectrum of myelodysplasia and myeloid leukemia. We compared genomic features of 159 childhood and adult AEL cases with non-AEL myeloid disorders and defined five age-related subgroups with distinct transcriptional profiles: adult, TP53 mutated; NPM1 mutated; KMT2A mutated/rearranged; adult, DDX41 mutated; and pediatric, NUP98 rearranged. Genomic features influenced outcome, with NPM1 mutations and HOXB9 overexpression being associated with a favorable prognosis and TP53, FLT3 or RB1 alterations associated with poor survival. Targetable signaling mutations were present in 45% of cases and included recurrent mutations of ALK and NTRK1, the latter of which drives erythroid leukemogenesis sensitive to TRK inhibition. This genomic landscape of AEL provides the framework for accurate diagnosis and risk stratification of this disease, and the rationale for testing targeted therapies in this high-risk leukemia.

Original languageEnglish
Pages (from-to)694-704
Number of pages11
JournalNature Genetics
Volume51
Issue number4
DOIs
Publication statusPublished - Apr 2019

Keywords

  • acute myeloid leukaemia
  • leukaemia

Cite this

Iacobucci, I., Wen, J., Meggendorfer, M., Choi, J. K., Shi, L., Pounds, S. B., ... Mullighan, C. G. (2019). Genomic subtyping and therapeutic targeting of acute erythroleukemia. Nature Genetics, 51(4), 694-704. https://doi.org/10.1038/s41588-019-0375-1
Iacobucci, Ilaria ; Wen, Ji ; Meggendorfer, Manja ; Choi, John K. ; Shi, Lei ; Pounds, Stanley B. ; Carmichael, Catherine L. ; Masih, Katherine E. ; Morris, Sarah M. ; Lindsley, R. Coleman ; Janke, Laura J. ; Alexander, Thomas B. ; Song, Guangchun ; Qu, Chunxu ; Li, Yongjin ; Payne-Turner, Debbie ; Tomizawa, Daisuke ; Kiyokawa, Nobutaka ; Valentine, Marcus ; Valentine, Virginia ; Basso, Giuseppe ; Locatelli, Franco ; Enemark, Eric J. ; Kham, Shirley K.Y. ; Yeoh, Allen E.J. ; Ma, Xiaotu ; Zhou, Xin ; Sioson, Edgar ; Rusch, Michael ; Ries, Rhonda E. ; Stieglitz, Elliot ; Hunger, Stephen P. ; Wei, Andrew H. ; To, L. Bik ; Lewis, Ian D. ; D’Andrea, Richard J. ; Kile, Benjamin T. ; Brown, Anna L. ; Scott, Hamish S. ; Hahn, Christopher N. ; Marlton, Paula ; Pei, Deqing ; Cheng, Cheng ; Loh, Mignon L. ; Ebert, Benjamin L. ; Meshinchi, Soheil ; Haferlach, Torsten ; Mullighan, Charles G. / Genomic subtyping and therapeutic targeting of acute erythroleukemia. In: Nature Genetics. 2019 ; Vol. 51, No. 4. pp. 694-704.
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abstract = "Acute erythroid leukemia (AEL) is a high-risk leukemia of poorly understood genetic basis, with controversy regarding diagnosis in the spectrum of myelodysplasia and myeloid leukemia. We compared genomic features of 159 childhood and adult AEL cases with non-AEL myeloid disorders and defined five age-related subgroups with distinct transcriptional profiles: adult, TP53 mutated; NPM1 mutated; KMT2A mutated/rearranged; adult, DDX41 mutated; and pediatric, NUP98 rearranged. Genomic features influenced outcome, with NPM1 mutations and HOXB9 overexpression being associated with a favorable prognosis and TP53, FLT3 or RB1 alterations associated with poor survival. Targetable signaling mutations were present in 45{\%} of cases and included recurrent mutations of ALK and NTRK1, the latter of which drives erythroid leukemogenesis sensitive to TRK inhibition. This genomic landscape of AEL provides the framework for accurate diagnosis and risk stratification of this disease, and the rationale for testing targeted therapies in this high-risk leukemia.",
keywords = "acute myeloid leukaemia, leukaemia",
author = "Ilaria Iacobucci and Ji Wen and Manja Meggendorfer and Choi, {John K.} and Lei Shi and Pounds, {Stanley B.} and Carmichael, {Catherine L.} and Masih, {Katherine E.} and Morris, {Sarah M.} and Lindsley, {R. Coleman} and Janke, {Laura J.} and Alexander, {Thomas B.} and Guangchun Song and Chunxu Qu and Yongjin Li and Debbie Payne-Turner and Daisuke Tomizawa and Nobutaka Kiyokawa and Marcus Valentine and Virginia Valentine and Giuseppe Basso and Franco Locatelli and Enemark, {Eric J.} and Kham, {Shirley K.Y.} and Yeoh, {Allen E.J.} and Xiaotu Ma and Xin Zhou and Edgar Sioson and Michael Rusch and Ries, {Rhonda E.} and Elliot Stieglitz and Hunger, {Stephen P.} and Wei, {Andrew H.} and To, {L. Bik} and Lewis, {Ian D.} and D’Andrea, {Richard J.} and Kile, {Benjamin T.} and Brown, {Anna L.} and Scott, {Hamish S.} and Hahn, {Christopher N.} and Paula Marlton and Deqing Pei and Cheng Cheng and Loh, {Mignon L.} and Ebert, {Benjamin L.} and Soheil Meshinchi and Torsten Haferlach and Mullighan, {Charles G.}",
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Iacobucci, I, Wen, J, Meggendorfer, M, Choi, JK, Shi, L, Pounds, SB, Carmichael, CL, Masih, KE, Morris, SM, Lindsley, RC, Janke, LJ, Alexander, TB, Song, G, Qu, C, Li, Y, Payne-Turner, D, Tomizawa, D, Kiyokawa, N, Valentine, M, Valentine, V, Basso, G, Locatelli, F, Enemark, EJ, Kham, SKY, Yeoh, AEJ, Ma, X, Zhou, X, Sioson, E, Rusch, M, Ries, RE, Stieglitz, E, Hunger, SP, Wei, AH, To, LB, Lewis, ID, D’Andrea, RJ, Kile, BT, Brown, AL, Scott, HS, Hahn, CN, Marlton, P, Pei, D, Cheng, C, Loh, ML, Ebert, BL, Meshinchi, S, Haferlach, T & Mullighan, CG 2019, 'Genomic subtyping and therapeutic targeting of acute erythroleukemia', Nature Genetics, vol. 51, no. 4, pp. 694-704. https://doi.org/10.1038/s41588-019-0375-1

Genomic subtyping and therapeutic targeting of acute erythroleukemia. / Iacobucci, Ilaria; Wen, Ji; Meggendorfer, Manja; Choi, John K.; Shi, Lei; Pounds, Stanley B.; Carmichael, Catherine L.; Masih, Katherine E.; Morris, Sarah M.; Lindsley, R. Coleman; Janke, Laura J.; Alexander, Thomas B.; Song, Guangchun; Qu, Chunxu; Li, Yongjin; Payne-Turner, Debbie; Tomizawa, Daisuke; Kiyokawa, Nobutaka; Valentine, Marcus; Valentine, Virginia; Basso, Giuseppe; Locatelli, Franco; Enemark, Eric J.; Kham, Shirley K.Y.; Yeoh, Allen E.J.; Ma, Xiaotu; Zhou, Xin; Sioson, Edgar; Rusch, Michael; Ries, Rhonda E.; Stieglitz, Elliot; Hunger, Stephen P.; Wei, Andrew H.; To, L. Bik; Lewis, Ian D.; D’Andrea, Richard J.; Kile, Benjamin T.; Brown, Anna L.; Scott, Hamish S.; Hahn, Christopher N.; Marlton, Paula; Pei, Deqing; Cheng, Cheng; Loh, Mignon L.; Ebert, Benjamin L.; Meshinchi, Soheil; Haferlach, Torsten; Mullighan, Charles G.

In: Nature Genetics, Vol. 51, No. 4, 04.2019, p. 694-704.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Genomic subtyping and therapeutic targeting of acute erythroleukemia

AU - Iacobucci, Ilaria

AU - Wen, Ji

AU - Meggendorfer, Manja

AU - Choi, John K.

AU - Shi, Lei

AU - Pounds, Stanley B.

AU - Carmichael, Catherine L.

AU - Masih, Katherine E.

AU - Morris, Sarah M.

AU - Lindsley, R. Coleman

AU - Janke, Laura J.

AU - Alexander, Thomas B.

AU - Song, Guangchun

AU - Qu, Chunxu

AU - Li, Yongjin

AU - Payne-Turner, Debbie

AU - Tomizawa, Daisuke

AU - Kiyokawa, Nobutaka

AU - Valentine, Marcus

AU - Valentine, Virginia

AU - Basso, Giuseppe

AU - Locatelli, Franco

AU - Enemark, Eric J.

AU - Kham, Shirley K.Y.

AU - Yeoh, Allen E.J.

AU - Ma, Xiaotu

AU - Zhou, Xin

AU - Sioson, Edgar

AU - Rusch, Michael

AU - Ries, Rhonda E.

AU - Stieglitz, Elliot

AU - Hunger, Stephen P.

AU - Wei, Andrew H.

AU - To, L. Bik

AU - Lewis, Ian D.

AU - D’Andrea, Richard J.

AU - Kile, Benjamin T.

AU - Brown, Anna L.

AU - Scott, Hamish S.

AU - Hahn, Christopher N.

AU - Marlton, Paula

AU - Pei, Deqing

AU - Cheng, Cheng

AU - Loh, Mignon L.

AU - Ebert, Benjamin L.

AU - Meshinchi, Soheil

AU - Haferlach, Torsten

AU - Mullighan, Charles G.

PY - 2019/4

Y1 - 2019/4

N2 - Acute erythroid leukemia (AEL) is a high-risk leukemia of poorly understood genetic basis, with controversy regarding diagnosis in the spectrum of myelodysplasia and myeloid leukemia. We compared genomic features of 159 childhood and adult AEL cases with non-AEL myeloid disorders and defined five age-related subgroups with distinct transcriptional profiles: adult, TP53 mutated; NPM1 mutated; KMT2A mutated/rearranged; adult, DDX41 mutated; and pediatric, NUP98 rearranged. Genomic features influenced outcome, with NPM1 mutations and HOXB9 overexpression being associated with a favorable prognosis and TP53, FLT3 or RB1 alterations associated with poor survival. Targetable signaling mutations were present in 45% of cases and included recurrent mutations of ALK and NTRK1, the latter of which drives erythroid leukemogenesis sensitive to TRK inhibition. This genomic landscape of AEL provides the framework for accurate diagnosis and risk stratification of this disease, and the rationale for testing targeted therapies in this high-risk leukemia.

AB - Acute erythroid leukemia (AEL) is a high-risk leukemia of poorly understood genetic basis, with controversy regarding diagnosis in the spectrum of myelodysplasia and myeloid leukemia. We compared genomic features of 159 childhood and adult AEL cases with non-AEL myeloid disorders and defined five age-related subgroups with distinct transcriptional profiles: adult, TP53 mutated; NPM1 mutated; KMT2A mutated/rearranged; adult, DDX41 mutated; and pediatric, NUP98 rearranged. Genomic features influenced outcome, with NPM1 mutations and HOXB9 overexpression being associated with a favorable prognosis and TP53, FLT3 or RB1 alterations associated with poor survival. Targetable signaling mutations were present in 45% of cases and included recurrent mutations of ALK and NTRK1, the latter of which drives erythroid leukemogenesis sensitive to TRK inhibition. This genomic landscape of AEL provides the framework for accurate diagnosis and risk stratification of this disease, and the rationale for testing targeted therapies in this high-risk leukemia.

KW - acute myeloid leukaemia

KW - leukaemia

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U2 - 10.1038/s41588-019-0375-1

DO - 10.1038/s41588-019-0375-1

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Iacobucci I, Wen J, Meggendorfer M, Choi JK, Shi L, Pounds SB et al. Genomic subtyping and therapeutic targeting of acute erythroleukemia. Nature Genetics. 2019 Apr;51(4):694-704. https://doi.org/10.1038/s41588-019-0375-1