Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML

Julia Maxson, Jason Gotlib, Daniel A. Pollyea, Angela G. Fleischman, Anupriya Agarwal, Christopher A. Eide, Daniel Bottomly, Beth Wilmot, Shannon McWeeney, Cristina E. Tognon, J. Blake Pond, Robert H. Collins, Basem Goueli, T. Oh Stephen, W. Deininger Michael, Bill Chang, Marc Loriaux, Brian Druker, Jeffrey Tyner

Research output: Contribution to journalArticle

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Abstract

BACKGROUND: The molecular causes of many hematologic cancers remain unclear. Among these cancers are chronic neutrophilic leukemia (CNL) and atypical (BCR-ABL1-negative) chronic myeloid leukemia (CML), both of which are diagnosed on the basis of neoplastic expansion of granulocytic cells and exclusion of genetic drivers that are known to occur in other myeloproliferative neoplasms and myeloproliferative- myelodysplastic overlap neoplasms. METHODS: To identify potential genetic drivers in these disorders, we used an integrated approach of deep sequencing coupled with the screening of primary leukemia cells obtained from patients with CNL or atypical CML against panels of tyrosine kinase-specific small interfering RNAs or small-molecule kinase inhibitors. We validated candidate oncogenes using in vitro transformation assays, and drug sensitivities were validated with the use of assays of primary-cell colonies. RESULTS: We identified activating mutations in the gene encoding the receptor for colony-stimulating factor 3 (CSF3R) in 16 of 27 patients (59%) with CNL or atypical CML. These mutations segregate within two distinct regions of CSF3R and lead to preferential downstream kinase signaling through SRC family-TNK2 or JAK kinases and differential sensitivity to kinase inhibitors. A patient with CNL carrying a JAK-activating CSF3R mutation had marked clinical improvement after the administration of the JAK1/2 inhibitor ruxolitinib. CONCLUSIONS: Mutations in CSF3R are common in patients with CNL or atypical CML and represent a potentially useful criterion for diagnosing these neoplasms. (Funded by the Leukemia and Lymphoma Society and others.)

Original languageEnglish (US)
Pages (from-to)1781-1790
Number of pages10
JournalNew England Journal of Medicine
Volume368
Issue number19
DOIs
StatePublished - 2013

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Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative
Leukemia, Neutrophilic, Chronic
Mutation
Phosphotransferases
Neoplasms
Leukemia
Colony-Stimulating Factor Receptors
Janus Kinases
High-Throughput Nucleotide Sequencing
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Oncogenes
Protein-Tyrosine Kinases
Small Interfering RNA
Lymphoma
Pharmaceutical Preparations
Genes

ASJC Scopus subject areas

  • Medicine(all)

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Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML. / Maxson, Julia; Gotlib, Jason; Pollyea, Daniel A.; Fleischman, Angela G.; Agarwal, Anupriya; Eide, Christopher A.; Bottomly, Daniel; Wilmot, Beth; McWeeney, Shannon; Tognon, Cristina E.; Pond, J. Blake; Collins, Robert H.; Goueli, Basem; Stephen, T. Oh; Michael, W. Deininger; Chang, Bill; Loriaux, Marc; Druker, Brian; Tyner, Jeffrey.

In: New England Journal of Medicine, Vol. 368, No. 19, 2013, p. 1781-1790.

Research output: Contribution to journalArticle

Maxson, J, Gotlib, J, Pollyea, DA, Fleischman, AG, Agarwal, A, Eide, CA, Bottomly, D, Wilmot, B, McWeeney, S, Tognon, CE, Pond, JB, Collins, RH, Goueli, B, Stephen, TO, Michael, WD, Chang, B, Loriaux, M, Druker, B & Tyner, J 2013, 'Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML', New England Journal of Medicine, vol. 368, no. 19, pp. 1781-1790. https://doi.org/10.1056/NEJMoa1214514
Maxson, Julia ; Gotlib, Jason ; Pollyea, Daniel A. ; Fleischman, Angela G. ; Agarwal, Anupriya ; Eide, Christopher A. ; Bottomly, Daniel ; Wilmot, Beth ; McWeeney, Shannon ; Tognon, Cristina E. ; Pond, J. Blake ; Collins, Robert H. ; Goueli, Basem ; Stephen, T. Oh ; Michael, W. Deininger ; Chang, Bill ; Loriaux, Marc ; Druker, Brian ; Tyner, Jeffrey. / Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML. In: New England Journal of Medicine. 2013 ; Vol. 368, No. 19. pp. 1781-1790.
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abstract = "BACKGROUND: The molecular causes of many hematologic cancers remain unclear. Among these cancers are chronic neutrophilic leukemia (CNL) and atypical (BCR-ABL1-negative) chronic myeloid leukemia (CML), both of which are diagnosed on the basis of neoplastic expansion of granulocytic cells and exclusion of genetic drivers that are known to occur in other myeloproliferative neoplasms and myeloproliferative- myelodysplastic overlap neoplasms. METHODS: To identify potential genetic drivers in these disorders, we used an integrated approach of deep sequencing coupled with the screening of primary leukemia cells obtained from patients with CNL or atypical CML against panels of tyrosine kinase-specific small interfering RNAs or small-molecule kinase inhibitors. We validated candidate oncogenes using in vitro transformation assays, and drug sensitivities were validated with the use of assays of primary-cell colonies. RESULTS: We identified activating mutations in the gene encoding the receptor for colony-stimulating factor 3 (CSF3R) in 16 of 27 patients (59{\%}) with CNL or atypical CML. These mutations segregate within two distinct regions of CSF3R and lead to preferential downstream kinase signaling through SRC family-TNK2 or JAK kinases and differential sensitivity to kinase inhibitors. A patient with CNL carrying a JAK-activating CSF3R mutation had marked clinical improvement after the administration of the JAK1/2 inhibitor ruxolitinib. CONCLUSIONS: Mutations in CSF3R are common in patients with CNL or atypical CML and represent a potentially useful criterion for diagnosing these neoplasms. (Funded by the Leukemia and Lymphoma Society and others.)",
author = "Julia Maxson and Jason Gotlib and Pollyea, {Daniel A.} and Fleischman, {Angela G.} and Anupriya Agarwal and Eide, {Christopher A.} and Daniel Bottomly and Beth Wilmot and Shannon McWeeney and Tognon, {Cristina E.} and Pond, {J. Blake} and Collins, {Robert H.} and Basem Goueli and Stephen, {T. Oh} and Michael, {W. Deininger} and Bill Chang and Marc Loriaux and Brian Druker and Jeffrey Tyner",
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T1 - Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML

AU - Maxson, Julia

AU - Gotlib, Jason

AU - Pollyea, Daniel A.

AU - Fleischman, Angela G.

AU - Agarwal, Anupriya

AU - Eide, Christopher A.

AU - Bottomly, Daniel

AU - Wilmot, Beth

AU - McWeeney, Shannon

AU - Tognon, Cristina E.

AU - Pond, J. Blake

AU - Collins, Robert H.

AU - Goueli, Basem

AU - Stephen, T. Oh

AU - Michael, W. Deininger

AU - Chang, Bill

AU - Loriaux, Marc

AU - Druker, Brian

AU - Tyner, Jeffrey

PY - 2013

Y1 - 2013

N2 - BACKGROUND: The molecular causes of many hematologic cancers remain unclear. Among these cancers are chronic neutrophilic leukemia (CNL) and atypical (BCR-ABL1-negative) chronic myeloid leukemia (CML), both of which are diagnosed on the basis of neoplastic expansion of granulocytic cells and exclusion of genetic drivers that are known to occur in other myeloproliferative neoplasms and myeloproliferative- myelodysplastic overlap neoplasms. METHODS: To identify potential genetic drivers in these disorders, we used an integrated approach of deep sequencing coupled with the screening of primary leukemia cells obtained from patients with CNL or atypical CML against panels of tyrosine kinase-specific small interfering RNAs or small-molecule kinase inhibitors. We validated candidate oncogenes using in vitro transformation assays, and drug sensitivities were validated with the use of assays of primary-cell colonies. RESULTS: We identified activating mutations in the gene encoding the receptor for colony-stimulating factor 3 (CSF3R) in 16 of 27 patients (59%) with CNL or atypical CML. These mutations segregate within two distinct regions of CSF3R and lead to preferential downstream kinase signaling through SRC family-TNK2 or JAK kinases and differential sensitivity to kinase inhibitors. A patient with CNL carrying a JAK-activating CSF3R mutation had marked clinical improvement after the administration of the JAK1/2 inhibitor ruxolitinib. CONCLUSIONS: Mutations in CSF3R are common in patients with CNL or atypical CML and represent a potentially useful criterion for diagnosing these neoplasms. (Funded by the Leukemia and Lymphoma Society and others.)

AB - BACKGROUND: The molecular causes of many hematologic cancers remain unclear. Among these cancers are chronic neutrophilic leukemia (CNL) and atypical (BCR-ABL1-negative) chronic myeloid leukemia (CML), both of which are diagnosed on the basis of neoplastic expansion of granulocytic cells and exclusion of genetic drivers that are known to occur in other myeloproliferative neoplasms and myeloproliferative- myelodysplastic overlap neoplasms. METHODS: To identify potential genetic drivers in these disorders, we used an integrated approach of deep sequencing coupled with the screening of primary leukemia cells obtained from patients with CNL or atypical CML against panels of tyrosine kinase-specific small interfering RNAs or small-molecule kinase inhibitors. We validated candidate oncogenes using in vitro transformation assays, and drug sensitivities were validated with the use of assays of primary-cell colonies. RESULTS: We identified activating mutations in the gene encoding the receptor for colony-stimulating factor 3 (CSF3R) in 16 of 27 patients (59%) with CNL or atypical CML. These mutations segregate within two distinct regions of CSF3R and lead to preferential downstream kinase signaling through SRC family-TNK2 or JAK kinases and differential sensitivity to kinase inhibitors. A patient with CNL carrying a JAK-activating CSF3R mutation had marked clinical improvement after the administration of the JAK1/2 inhibitor ruxolitinib. CONCLUSIONS: Mutations in CSF3R are common in patients with CNL or atypical CML and represent a potentially useful criterion for diagnosing these neoplasms. (Funded by the Leukemia and Lymphoma Society and others.)

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DO - 10.1056/NEJMoa1214514

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