Novel germ line DDX41 mutations define families with a lower age of MDS/AML onset and lymphoid malignancies

Maya Lewinsohn, Anna L. Brown, Luke M. Weinel, Connie Phung, George Rafidi, Ming K. Lee, Andreas W. Schreiber, Jinghua Feng, Milena Babic, Chan Eng Chong, Young Lee, Agnes Yong, Graeme K. Suthers, Nicola Poplawski, Meryl Altree, Kerry Phillips, Louise Jaensch, Miriam Fine, Richard J. D'Andrea, Ian D. Lewis & 10 others Bruno C. Medeiros, Daniel A. Pollyea, Mary Claire King, Tom Walsh, Siobán Keel, Akiko Shimamura, Lucy A. Godley, Christopher N. Hahn, Jane E. Churpek, Hamish S. Scott

Research output: Contribution to journalArticle

69 Citations (Scopus)

Abstract

Recently our group and others have identified DDX41 mutations both as germ line and acquired somatic mutations in families with multiple cases of late onset myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML), suggesting that DDX41 acts as a tumor suppressor. To determine whether novel DDX41 mutations could be identified in families with additional types of hematologic malignancies, our group screened two cohorts of families with a diverse range of hematologic malignancy subtypes. Among 289 families, we identified nine (3%) with DDX41 mutations. As previously observed, MDS and AML were the most common malignancies, often of the erythroblastic subtype, and 1 family displayed early-onset follicular lymphoma. Five novelmutations were identified, including missensemutations within important functional domains and start-loss and splicingmutations predicted to result in truncated proteins.We also show that most asymptomatic mutation carriers have normal blood counts until malignancy develops. This study expands both the mutation and phenotypic spectra observed in families with germ line DDX41 mutations. With an increasing number of both inheritedand acquiredmutations in thisgene being identified, further studyof howDDX41 disruption leads to hematologicmalignancies is critical.

LanguageEnglish
Pages1017-1023
Number of pages7
JournalBlood
Volume127
Issue number8
DOIs
Publication statusPublished - 25 Feb 2016

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Lewinsohn, M., Brown, A. L., Weinel, L. M., Phung, C., Rafidi, G., Lee, M. K., ... Scott, H. S. (2016). Novel germ line DDX41 mutations define families with a lower age of MDS/AML onset and lymphoid malignancies. Blood, 127(8), 1017-1023. https://doi.org/10.1182/blood-2015-10-676098
Lewinsohn, Maya ; Brown, Anna L. ; Weinel, Luke M. ; Phung, Connie ; Rafidi, George ; Lee, Ming K. ; Schreiber, Andreas W. ; Feng, Jinghua ; Babic, Milena ; Chong, Chan Eng ; Lee, Young ; Yong, Agnes ; Suthers, Graeme K. ; Poplawski, Nicola ; Altree, Meryl ; Phillips, Kerry ; Jaensch, Louise ; Fine, Miriam ; D'Andrea, Richard J. ; Lewis, Ian D. ; Medeiros, Bruno C. ; Pollyea, Daniel A. ; King, Mary Claire ; Walsh, Tom ; Keel, Siobán ; Shimamura, Akiko ; Godley, Lucy A. ; Hahn, Christopher N. ; Churpek, Jane E. ; Scott, Hamish S. / Novel germ line DDX41 mutations define families with a lower age of MDS/AML onset and lymphoid malignancies. In: Blood. 2016 ; Vol. 127, No. 8. pp. 1017-1023.
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abstract = "Recently our group and others have identified DDX41 mutations both as germ line and acquired somatic mutations in families with multiple cases of late onset myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML), suggesting that DDX41 acts as a tumor suppressor. To determine whether novel DDX41 mutations could be identified in families with additional types of hematologic malignancies, our group screened two cohorts of families with a diverse range of hematologic malignancy subtypes. Among 289 families, we identified nine (3{\%}) with DDX41 mutations. As previously observed, MDS and AML were the most common malignancies, often of the erythroblastic subtype, and 1 family displayed early-onset follicular lymphoma. Five novelmutations were identified, including missensemutations within important functional domains and start-loss and splicingmutations predicted to result in truncated proteins.We also show that most asymptomatic mutation carriers have normal blood counts until malignancy develops. This study expands both the mutation and phenotypic spectra observed in families with germ line DDX41 mutations. With an increasing number of both inheritedand acquiredmutations in thisgene being identified, further studyof howDDX41 disruption leads to hematologicmalignancies is critical.",
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Lewinsohn, M, Brown, AL, Weinel, LM, Phung, C, Rafidi, G, Lee, MK, Schreiber, AW, Feng, J, Babic, M, Chong, CE, Lee, Y, Yong, A, Suthers, GK, Poplawski, N, Altree, M, Phillips, K, Jaensch, L, Fine, M, D'Andrea, RJ, Lewis, ID, Medeiros, BC, Pollyea, DA, King, MC, Walsh, T, Keel, S, Shimamura, A, Godley, LA, Hahn, CN, Churpek, JE & Scott, HS 2016, 'Novel germ line DDX41 mutations define families with a lower age of MDS/AML onset and lymphoid malignancies', Blood, vol. 127, no. 8, pp. 1017-1023. https://doi.org/10.1182/blood-2015-10-676098

Novel germ line DDX41 mutations define families with a lower age of MDS/AML onset and lymphoid malignancies. / Lewinsohn, Maya; Brown, Anna L.; Weinel, Luke M.; Phung, Connie; Rafidi, George; Lee, Ming K.; Schreiber, Andreas W.; Feng, Jinghua; Babic, Milena; Chong, Chan Eng; Lee, Young; Yong, Agnes; Suthers, Graeme K.; Poplawski, Nicola; Altree, Meryl; Phillips, Kerry; Jaensch, Louise; Fine, Miriam; D'Andrea, Richard J.; Lewis, Ian D.; Medeiros, Bruno C.; Pollyea, Daniel A.; King, Mary Claire; Walsh, Tom; Keel, Siobán; Shimamura, Akiko; Godley, Lucy A.; Hahn, Christopher N.; Churpek, Jane E.; Scott, Hamish S.

In: Blood, Vol. 127, No. 8, 25.02.2016, p. 1017-1023.

Research output: Contribution to journalArticle

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AU - Brown, Anna L.

AU - Weinel, Luke M.

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AU - Lee, Ming K.

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AU - Chong, Chan Eng

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AU - Yong, Agnes

AU - Suthers, Graeme K.

AU - Poplawski, Nicola

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AU - Phillips, Kerry

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AU - Fine, Miriam

AU - D'Andrea, Richard J.

AU - Lewis, Ian D.

AU - Medeiros, Bruno C.

AU - Pollyea, Daniel A.

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AU - Walsh, Tom

AU - Keel, Siobán

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AU - Scott, Hamish S.

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AB - Recently our group and others have identified DDX41 mutations both as germ line and acquired somatic mutations in families with multiple cases of late onset myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML), suggesting that DDX41 acts as a tumor suppressor. To determine whether novel DDX41 mutations could be identified in families with additional types of hematologic malignancies, our group screened two cohorts of families with a diverse range of hematologic malignancy subtypes. Among 289 families, we identified nine (3%) with DDX41 mutations. As previously observed, MDS and AML were the most common malignancies, often of the erythroblastic subtype, and 1 family displayed early-onset follicular lymphoma. Five novelmutations were identified, including missensemutations within important functional domains and start-loss and splicingmutations predicted to result in truncated proteins.We also show that most asymptomatic mutation carriers have normal blood counts until malignancy develops. This study expands both the mutation and phenotypic spectra observed in families with germ line DDX41 mutations. With an increasing number of both inheritedand acquiredmutations in thisgene being identified, further studyof howDDX41 disruption leads to hematologicmalignancies is critical.

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