Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic Leukemia

Charlotte M. Niemeyer; Michelle W. Kang; Danielle H. Shin; Ingrid Furlan; Miriam Erlacher; Nancy J. Bunin; Severa Bunda; Jerry Z. Finklestein; Kathleen M. Sakamoto; Thomas A. Gorr; Parinda Mehta; Irene Schmid; Gabriele Kropshofer; Selim Corbacioglu; Peter J. Lang; Christoph Klein; Paul Gerhard Schlegel; Andrea Heinzmann; Michaela Schneider; Jan Starý; Marry M.Den van Heuvel-Eibrink; Henrik Hasle; Franco Locatelli; Debbie Sakai; Sophie Archambeault; Leslie Chen; Ryan C. Russell; Stephanie S. Sybingco; Michael Ohh; Benjamin S. Braun; Christian Flotho; Mignon L. Loh

doi:10.1038/ng.641

Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic Leukemia

Charlotte M. Niemeyer, Michelle W. Kang, Danielle H. Shin, Ingrid Furlan, Miriam Erlacher, Nancy J. Bunin, Severa Bunda, Jerry Z. Finklestein, Kathleen M. Sakamoto, Thomas A. Gorr, Parinda Mehta, Irene Schmid, Gabriele Kropshofer, Selim Corbacioglu, Peter J. Lang, Christoph Klein, Paul Gerhard Schlegel, Andrea Heinzmann, Michaela Schneider, Jan StarýMarry M.Den van Heuvel-Eibrink, Henrik Hasle, Franco Locatelli, Debbie Sakai, Sophie Archambeault, Leslie Chen, Ryan C. Russell, Stephanie S. Sybingco, Michael Ohh, Benjamin S. Braun, Christian Flotho, Mignon L. Loh

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Abstract

CBL encodes a member of the Cbl family of proteins, which functions as an E3 ubiquitin ligase. We describe a dominant developmental disorder resulting from germline missense CBL mutations, which is characterized by impaired growth, developmental delay, cryptorchidism and a predisposition to juvenile myelomonocytic leukemia (JMML). Some individuals experienced spontaneous regression of their JMML but developed vasculitis later in life. Importantly, JMML specimens from affected children show loss of the normal CBL allele through acquired isodisomy. Consistent with these genetic data, the common p.371Y>H altered Cbl protein induces cytokine-independent growth and constitutive phosphorylation of ERK, AKT and S6 only in hematopoietic cells in which normal Cbl expression is reduced by RNA interference. We conclude that germline CBL mutations have developmental, tumorigenic and functional consequences that resemble disorders that are caused by hyperactive Ras/Raf/MEK/ERK signaling and include neurofibromatosis type 1, Noonan syndrome, Costello syndrome, cardiofaciocutaneous syndrome and Legius syndrome.

Original language	English
Pages (from-to)	641
Number of pages	1
Journal	Nature Genetics
Volume	42
Issue number	9
DOIs	https://doi.org/10.1038/ng.641
Publication status	Published - 1 Sept 2010
Externally published	Yes

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Niemeyer, C. M., Kang, M. W., Shin, D. H., Furlan, I., Erlacher, M., Bunin, N. J., Bunda, S., Finklestein, J. Z., Sakamoto, K. M., Gorr, T. A., Mehta, P., Schmid, I., Kropshofer, G., Corbacioglu, S., Lang, P. J., Klein, C., Schlegel, P. G., Heinzmann, A., Schneider, M., ... Loh, M. L. (2010). Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic Leukemia. Nature Genetics, 42(9), 641. https://doi.org/10.1038/ng.641

@article{93b77db6a41141caafbd492f08d67205,

title = "Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic Leukemia",

abstract = "CBL encodes a member of the Cbl family of proteins, which functions as an E3 ubiquitin ligase. We describe a dominant developmental disorder resulting from germline missense CBL mutations, which is characterized by impaired growth, developmental delay, cryptorchidism and a predisposition to juvenile myelomonocytic leukemia (JMML). Some individuals experienced spontaneous regression of their JMML but developed vasculitis later in life. Importantly, JMML specimens from affected children show loss of the normal CBL allele through acquired isodisomy. Consistent with these genetic data, the common p.371Y>H altered Cbl protein induces cytokine-independent growth and constitutive phosphorylation of ERK, AKT and S6 only in hematopoietic cells in which normal Cbl expression is reduced by RNA interference. We conclude that germline CBL mutations have developmental, tumorigenic and functional consequences that resemble disorders that are caused by hyperactive Ras/Raf/MEK/ERK signaling and include neurofibromatosis type 1, Noonan syndrome, Costello syndrome, cardiofaciocutaneous syndrome and Legius syndrome.",

author = "Niemeyer, {Charlotte M.} and Kang, {Michelle W.} and Shin, {Danielle H.} and Ingrid Furlan and Miriam Erlacher and Bunin, {Nancy J.} and Severa Bunda and Finklestein, {Jerry Z.} and Sakamoto, {Kathleen M.} and Gorr, {Thomas A.} and Parinda Mehta and Irene Schmid and Gabriele Kropshofer and Selim Corbacioglu and Lang, {Peter J.} and Christoph Klein and Schlegel, {Paul Gerhard} and Andrea Heinzmann and Michaela Schneider and Jan Star{\'y} and {van Heuvel-Eibrink}, {Marry M.Den} and Henrik Hasle and Franco Locatelli and Debbie Sakai and Sophie Archambeault and Leslie Chen and Russell, {Ryan C.} and Sybingco, {Stephanie S.} and Michael Ohh and Braun, {Benjamin S.} and Christian Flotho and Loh, {Mignon L.}",

note = "Funding Information: We gratefully acknowledge the generous participation of the families included in this report. Supported in part by the US National Institutes of Health (CA113557 to M.L.L.); the V Foundation for Cancer Research (M.L.L. and B.S.B.); NIH/NCI (K08 CA103868 to B.S.B., R01 CA104282 to M.L.L. and B.S.B.); The Leukemia Lymphoma Society (6059-09, 2157-08 to M.L.L.); the Frank A. Campini Foundation (M.L.L. and B.S.B.); The Concern Foundation (B.S.B.); Deutsche Forschungsgemeinschaft (KR3473/1-1 to C.F.); Deutsche Krebshilfe (108220 to C.M.N. and C.F.); Deutsche Jos{\'e} Carreras Leuk{\"a}mie-Stiftung (R08/19 to C.F.); the Canadian Cancer Society (16056 to M.O.); and the National Institute of General Medical Sciences (T32GM007618 to D.H.S.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of General Medical Sciences or the National Institutes of Health.",

year = "2010",

month = sep,

day = "1",

doi = "10.1038/ng.641",

language = "English",

volume = "42",

pages = "641",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "9",

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Niemeyer, CM, Kang, MW, Shin, DH, Furlan, I, Erlacher, M, Bunin, NJ, Bunda, S, Finklestein, JZ, Sakamoto, KM, Gorr, TA, Mehta, P, Schmid, I, Kropshofer, G, Corbacioglu, S, Lang, PJ, Klein, C, Schlegel, PG, Heinzmann, A, Schneider, M, Starý, J, van Heuvel-Eibrink, MMD, Hasle, H, Locatelli, F, Sakai, D, Archambeault, S, Chen, L, Russell, RC, Sybingco, SS, Ohh, M, Braun, BS, Flotho, C & Loh, ML 2010, 'Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic Leukemia', Nature Genetics, vol. 42, no. 9, pp. 641. https://doi.org/10.1038/ng.641

TY - JOUR

T1 - Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic Leukemia

AU - Niemeyer, Charlotte M.

AU - Kang, Michelle W.

AU - Shin, Danielle H.

AU - Furlan, Ingrid

AU - Erlacher, Miriam

AU - Bunin, Nancy J.

AU - Bunda, Severa

AU - Finklestein, Jerry Z.

AU - Sakamoto, Kathleen M.

AU - Gorr, Thomas A.

AU - Mehta, Parinda

AU - Schmid, Irene

AU - Kropshofer, Gabriele

AU - Corbacioglu, Selim

AU - Lang, Peter J.

AU - Klein, Christoph

AU - Schlegel, Paul Gerhard

AU - Heinzmann, Andrea

AU - Schneider, Michaela

AU - Starý, Jan

AU - van Heuvel-Eibrink, Marry M.Den

AU - Hasle, Henrik

AU - Locatelli, Franco

AU - Sakai, Debbie

AU - Archambeault, Sophie

AU - Chen, Leslie

AU - Russell, Ryan C.

AU - Sybingco, Stephanie S.

AU - Ohh, Michael

AU - Braun, Benjamin S.

AU - Flotho, Christian

AU - Loh, Mignon L.

N1 - Funding Information: We gratefully acknowledge the generous participation of the families included in this report. Supported in part by the US National Institutes of Health (CA113557 to M.L.L.); the V Foundation for Cancer Research (M.L.L. and B.S.B.); NIH/NCI (K08 CA103868 to B.S.B., R01 CA104282 to M.L.L. and B.S.B.); The Leukemia Lymphoma Society (6059-09, 2157-08 to M.L.L.); the Frank A. Campini Foundation (M.L.L. and B.S.B.); The Concern Foundation (B.S.B.); Deutsche Forschungsgemeinschaft (KR3473/1-1 to C.F.); Deutsche Krebshilfe (108220 to C.M.N. and C.F.); Deutsche José Carreras Leukämie-Stiftung (R08/19 to C.F.); the Canadian Cancer Society (16056 to M.O.); and the National Institute of General Medical Sciences (T32GM007618 to D.H.S.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of General Medical Sciences or the National Institutes of Health.

PY - 2010/9/1

Y1 - 2010/9/1

N2 - CBL encodes a member of the Cbl family of proteins, which functions as an E3 ubiquitin ligase. We describe a dominant developmental disorder resulting from germline missense CBL mutations, which is characterized by impaired growth, developmental delay, cryptorchidism and a predisposition to juvenile myelomonocytic leukemia (JMML). Some individuals experienced spontaneous regression of their JMML but developed vasculitis later in life. Importantly, JMML specimens from affected children show loss of the normal CBL allele through acquired isodisomy. Consistent with these genetic data, the common p.371Y>H altered Cbl protein induces cytokine-independent growth and constitutive phosphorylation of ERK, AKT and S6 only in hematopoietic cells in which normal Cbl expression is reduced by RNA interference. We conclude that germline CBL mutations have developmental, tumorigenic and functional consequences that resemble disorders that are caused by hyperactive Ras/Raf/MEK/ERK signaling and include neurofibromatosis type 1, Noonan syndrome, Costello syndrome, cardiofaciocutaneous syndrome and Legius syndrome.

AB - CBL encodes a member of the Cbl family of proteins, which functions as an E3 ubiquitin ligase. We describe a dominant developmental disorder resulting from germline missense CBL mutations, which is characterized by impaired growth, developmental delay, cryptorchidism and a predisposition to juvenile myelomonocytic leukemia (JMML). Some individuals experienced spontaneous regression of their JMML but developed vasculitis later in life. Importantly, JMML specimens from affected children show loss of the normal CBL allele through acquired isodisomy. Consistent with these genetic data, the common p.371Y>H altered Cbl protein induces cytokine-independent growth and constitutive phosphorylation of ERK, AKT and S6 only in hematopoietic cells in which normal Cbl expression is reduced by RNA interference. We conclude that germline CBL mutations have developmental, tumorigenic and functional consequences that resemble disorders that are caused by hyperactive Ras/Raf/MEK/ERK signaling and include neurofibromatosis type 1, Noonan syndrome, Costello syndrome, cardiofaciocutaneous syndrome and Legius syndrome.

UR - http://www.scopus.com/inward/record.url?scp=84984935016&partnerID=8YFLogxK

U2 - 10.1038/ng.641

DO - 10.1038/ng.641

M3 - Article

C2 - 20694012

AN - SCOPUS:84984935016

SN - 1061-4036

VL - 42

SP - 641

JO - Nature Genetics

JF - Nature Genetics

IS - 9

ER -

Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic Leukemia

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