The genomic landscape of juvenile myelomonocytic leukemia

Elliot Stieglitz; Amaro N. Taylor-Weiner; Tiffany Y. Chang; Laura C. Gelston; Yong Dong Wang; Tali Mazor; Emilio Esquivel; Ariel Yu; Sara Seepo; Scott R. Olsen; Mara Rosenberg; Sophie L. Archambeault; Ghada Abusin; Kyle Beckman; Patrick A. Brown; Michael Briones; Benjamin Carcamo; Todd Cooper; Gary V. Dahl; Peter D. Emanuel; Mark N. Fluchel; Rakesh K. Goyal; Robert J. Hayashi; Johann Hitzler; Christopher Hugge; Y. Lucy Liu; Yoav H. Messinger; Donald H. Mahoney; Philip Monteleone; Eneida R. Nemecek; Philip A. Roehrs; Reuven J. Schore; Kimo C. Stine; Clifford M. Takemoto; Jeffrey A. Toretsky; Joseph F. Costello; Adam B. Olshen; Chip Stewart; Yongjin Li; Jing Ma; Robert B. Gerbing; Todd A. Alonzo; Gad Getz; Tanja A. Gruber; Todd R. Golub; Kimberly Stegmaier; Mignon L. Loh

doi:10.1038/ng.3400

The genomic landscape of juvenile myelomonocytic leukemia

Elliot Stieglitz, Amaro N. Taylor-Weiner, Tiffany Y. Chang, Laura C. Gelston, Yong Dong Wang, Tali Mazor, Emilio Esquivel, Ariel Yu, Sara Seepo, Scott R. Olsen, Mara Rosenberg, Sophie L. Archambeault, Ghada Abusin, Kyle Beckman, Patrick A. Brown, Michael Briones, Benjamin Carcamo, Todd Cooper, Gary V. Dahl, Peter D. EmanuelMark N. Fluchel, Rakesh K. Goyal, Robert J. Hayashi, Johann Hitzler, Christopher Hugge, Y. Lucy Liu, Yoav H. Messinger, Donald H. Mahoney, Philip Monteleone, Eneida R. Nemecek, Philip A. Roehrs, Reuven J. Schore, Kimo C. Stine, Clifford M. Takemoto, Jeffrey A. Toretsky, Joseph F. Costello, Adam B. Olshen, Chip Stewart, Yongjin Li, Jing Ma, Robert B. Gerbing, Todd A. Alonzo, Gad Getz, Tanja A. Gruber, Todd R. Golub, Kimberly Stegmaier, Mignon L. Loh

Pediatric Hematology and Oncology

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

208 Scopus citations

Abstract

Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative neoplasm (MPN) of childhood with a poor prognosis. Mutations in NF1, NRAS, KRAS, PTPN11 or CBL occur in 85% of patients, yet there are currently no risk stratification algorithms capable of predicting which patients will be refractory to conventional treatment and could therefore be candidates for experimental therapies. In addition, few molecular pathways aside from the RAS-MAPK pathway have been identified that could serve as the basis for such novel therapeutic strategies. We therefore sought to genomically characterize serial samples from patients at diagnosis through relapse and transformation to acute myeloid leukemia to expand knowledge of the mutational spectrum in JMML. We identified recurrent mutations in genes involved in signal transduction, splicing, Polycomb repressive complex 2 (PRC2) and transcription. Notably, the number of somatic alterations present at diagnosis appears to be the major determinant of outcome.

Original language	English (US)
Pages (from-to)	1326-1333
Number of pages	8
Journal	Nature genetics
Volume	47
Issue number	11
DOIs	https://doi.org/10.1038/ng.3400
State	Published - Nov 1 2015

ASJC Scopus subject areas

Genetics

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Stieglitz, E., Taylor-Weiner, A. N., Chang, T. Y., Gelston, L. C., Wang, Y. D., Mazor, T., Esquivel, E., Yu, A., Seepo, S., Olsen, S. R., Rosenberg, M., Archambeault, S. L., Abusin, G., Beckman, K., Brown, P. A., Briones, M., Carcamo, B., Cooper, T., Dahl, G. V., ... Loh, M. L. (2015). The genomic landscape of juvenile myelomonocytic leukemia. Nature genetics, 47(11), 1326-1333. https://doi.org/10.1038/ng.3400

Stieglitz, E, Taylor-Weiner, AN, Chang, TY, Gelston, LC, Wang, YD, Mazor, T, Esquivel, E, Yu, A, Seepo, S, Olsen, SR, Rosenberg, M, Archambeault, SL, Abusin, G, Beckman, K, Brown, PA, Briones, M, Carcamo, B, Cooper, T, Dahl, GV, Emanuel, PD, Fluchel, MN, Goyal, RK, Hayashi, RJ, Hitzler, J, Hugge, C, Liu, YL, Messinger, YH, Mahoney, DH, Monteleone, P, Nemecek, ER, Roehrs, PA, Schore, RJ, Stine, KC, Takemoto, CM, Toretsky, JA, Costello, JF, Olshen, AB, Stewart, C, Li, Y, Ma, J, Gerbing, RB, Alonzo, TA, Getz, G, Gruber, TA, Golub, TR, Stegmaier, K & Loh, ML 2015, 'The genomic landscape of juvenile myelomonocytic leukemia', Nature genetics, vol. 47, no. 11, pp. 1326-1333. https://doi.org/10.1038/ng.3400

@article{71559dc1835f4b76ae2637017b798c20,

title = "The genomic landscape of juvenile myelomonocytic leukemia",

abstract = "Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative neoplasm (MPN) of childhood with a poor prognosis. Mutations in NF1, NRAS, KRAS, PTPN11 or CBL occur in 85% of patients, yet there are currently no risk stratification algorithms capable of predicting which patients will be refractory to conventional treatment and could therefore be candidates for experimental therapies. In addition, few molecular pathways aside from the RAS-MAPK pathway have been identified that could serve as the basis for such novel therapeutic strategies. We therefore sought to genomically characterize serial samples from patients at diagnosis through relapse and transformation to acute myeloid leukemia to expand knowledge of the mutational spectrum in JMML. We identified recurrent mutations in genes involved in signal transduction, splicing, Polycomb repressive complex 2 (PRC2) and transcription. Notably, the number of somatic alterations present at diagnosis appears to be the major determinant of outcome.",

author = "Elliot Stieglitz and Taylor-Weiner, {Amaro N.} and Chang, {Tiffany Y.} and Gelston, {Laura C.} and Wang, {Yong Dong} and Tali Mazor and Emilio Esquivel and Ariel Yu and Sara Seepo and Olsen, {Scott R.} and Mara Rosenberg and Archambeault, {Sophie L.} and Ghada Abusin and Kyle Beckman and Brown, {Patrick A.} and Michael Briones and Benjamin Carcamo and Todd Cooper and Dahl, {Gary V.} and Emanuel, {Peter D.} and Fluchel, {Mark N.} and Goyal, {Rakesh K.} and Hayashi, {Robert J.} and Johann Hitzler and Christopher Hugge and Liu, {Y. Lucy} and Messinger, {Yoav H.} and Mahoney, {Donald H.} and Philip Monteleone and Nemecek, {Eneida R.} and Roehrs, {Philip A.} and Schore, {Reuven J.} and Stine, {Kimo C.} and Takemoto, {Clifford M.} and Toretsky, {Jeffrey A.} and Costello, {Joseph F.} and Olshen, {Adam B.} and Chip Stewart and Yongjin Li and Jing Ma and Gerbing, {Robert B.} and Alonzo, {Todd A.} and Gad Getz and Gruber, {Tanja A.} and Golub, {Todd R.} and Kimberly Stegmaier and Loh, {Mignon L.}",

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AU - Taylor-Weiner, Amaro N.

AU - Chang, Tiffany Y.

AU - Gelston, Laura C.

AU - Wang, Yong Dong

AU - Mazor, Tali

AU - Esquivel, Emilio

AU - Yu, Ariel

AU - Seepo, Sara

AU - Olsen, Scott R.

AU - Rosenberg, Mara

AU - Archambeault, Sophie L.

AU - Abusin, Ghada

AU - Beckman, Kyle

AU - Brown, Patrick A.

AU - Briones, Michael

AU - Carcamo, Benjamin

AU - Cooper, Todd

AU - Dahl, Gary V.

AU - Emanuel, Peter D.

AU - Fluchel, Mark N.

AU - Goyal, Rakesh K.

AU - Hayashi, Robert J.

AU - Hitzler, Johann

AU - Hugge, Christopher

AU - Liu, Y. Lucy

AU - Messinger, Yoav H.

AU - Mahoney, Donald H.

AU - Monteleone, Philip

AU - Nemecek, Eneida R.

AU - Roehrs, Philip A.

AU - Schore, Reuven J.

AU - Stine, Kimo C.

AU - Takemoto, Clifford M.

AU - Toretsky, Jeffrey A.

AU - Costello, Joseph F.

AU - Olshen, Adam B.

AU - Stewart, Chip

AU - Li, Yongjin

AU - Ma, Jing

AU - Gerbing, Robert B.

AU - Alonzo, Todd A.

AU - Getz, Gad

AU - Gruber, Tanja A.

AU - Golub, Todd R.

AU - Stegmaier, Kimberly

AU - Loh, Mignon L.

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The genomic landscape of juvenile myelomonocytic leukemia

Abstract

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