Nf1 deficiency causes ras-dediated granulocyte/macrophage colony stimulating factor hypersensitivity and chronic myeloid leukaemia

ABSTRACT The Ras signal transduction pathway is often deregulated in human myeloid leukaemia. For example, activating point mutations in _RAS_ genes are found in some patients with juvenile

chronic myelogenous leukaemia (JCML), while other patients with JCML show loss of the neurofibromatosis type 1 (_NF1_) gene, a Ras GTPase activating protein. By generating mice whose

haematopoietic system is reconsituted with _NF1_ deficient haematopoietic stem cells we show that _NF1_ gene loss, by itself, is sufficient to produce the myeloproliferative symptoms

associated with human JCML. We also provide evidence to indicate that _NF1_ gene loss induces myeloproliferative disease through a Ras-mediated hypersensitivity to

granulocyte/macrophage-colony stimulating factor (GM-CSF). Finally, we describe a genetic screen for identifying genes that cooperate with _NF1_ gene loss during progression to acute myeloid

leukaemia. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your institution Subscribe

to this journal Receive 12 print issues and online access $209.00 per year only $17.42 per issue Learn more Buy this article * Purchase on SpringerLink * Instant access to full article PDF

Buy now Prices may be subject to local taxes which are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact

customer support SIMILAR CONTENT BEING VIEWED BY OTHERS ONCOGENIC AND MICROENVIRONMENTAL SIGNALS DRIVE CELL TYPE SPECIFIC APOPTOSIS RESISTANCE IN JUVENILE MYELOMONOCYTIC LEUKEMIA Article

Open access 08 March 2025 ONCOGENIC RAS PROMOTES LEUKEMIC TRANSFORMATION OF CUX1-DEFICIENT CELLS Article 01 February 2023 RHO GTPASES: FROM NEW PARTNERS TO COMPLEX IMMUNE SYNDROMES Article

05 February 2021 REFERENCES * Riccardi, V.M. In _Neurofibromatosis: phenotype, natural history, and pathogenesis_. (Johns Hopkins Press, Baltimore, 1992). Google Scholar  * Bader, J.L.

Neurofibromatosis and cancer. _Ann. N. Y. Acad. Sci._ 486, 56–65 (1986). Article  Google Scholar  * Hope, D.G. & Mulvihill, J.J. Malignancy in neunofibromatosis. _Adv. Neurol._ 29, 33–56

(1981). CAS  PubMed  Google Scholar  * Bader, J.L. & Miller, R.W. Neurofibromatosis and childhood leukemia. _J. Pediat._ 92, 925–929 (1978). Article  CAS  PubMed  Google Scholar  *

Gutmann, D.H. & Collins, F.S. The neurofibromatosis type 1 gene and its protein product, neurofibromin. _Neuron_ 10, 335–343 (1993). Article  CAS  PubMed  Google Scholar  * Barbacid, M.

Ras oncogenes: their role in neoplasia. _Eur. J. Clin. Invest._ 20, 225–235 (1990). Article  CAS  PubMed  Google Scholar  * Johnson, M.R., Look, A.T., DeClue, J.E., Valentine, M.B. &

Lowy, D.R. Inactivation of the _NF1_ gene in human melanoma and neuroblastoma cell lines without impaired regulation of GTP–Ras. _Proc. Natl. Acad. Sci. USA_ 90, 5539–5543 (1993). Article 

CAS  PubMed  PubMed Central  Google Scholar  * Johnson, M.R. _et al_. Neurofibromin can inhibit ras-dependent growth by a mechanism independent of its GTPase-accelerating function. _Molec.

cell. Biol._ 14, 641–645 (1994). Article  CAS  PubMed  PubMed Central  Google Scholar  * Shannon, K.M. _et al_. Loss of the normal _NF1_ allele from the bone marrow of children with type 1

neurofibromatosis and malignant myeloid disorders. _New Engl. J. Med._ 330, 597–601 (1994). Article  CAS  PubMed  Google Scholar  * Jacks, T. _et al_. Tumor predisposition in mice

heterozygous for a targeted mutation in _Nf1_. _Nature Genet._ 7, 353–361 (1994). Article  CAS  PubMed  Google Scholar  * Buchberg, A.M., Bedigian, H.G., Jenkins, N.A. & Copeland, N.G.,

_Evi_-2, a common integration site involved in murine myeloid leukemogenesis. _Molec. Cell. Biol._ 10, 4658–4666 (1990). Article  CAS  PubMed  PubMed Central  Google Scholar  * Largaespada,

D.A., Shaughnessy, J.D., Jenkins, N.A. & Copeland, N.G. Retroviral insertion at the _Evi_-2 locus in BXH-2 myeloid leukemia cell lines disrupts _Nf1_ expression without changes in steady

state ras-GTP levels. _J. Virol._ 69, 5095–5102 (1995). CAS  PubMed  PubMed Central  Google Scholar  * Kalra, R., Paderanga, D.C., Olson, K. & Shannon, K.M. Genetic analysis is

consistent with the hypothesis that NF1 limits myeloid growth through p21 ras. _Blood_ 84, 3435–3439 (1994). CAS  PubMed  Google Scholar  * Brannan, C.I. _et al_. Targeted disruption of the

neurofibromatosis type-1 gene leads to developmental abnormalities in heart and various neural crest-derived tissues. _Genes Dev._ 8, 1019–1029 (1994). Article  CAS  PubMed  Google Scholar 

* Moore, M.A.S., McNeill, T.A. & Haskill, J.S. Density distribution analysis of in vivo and in vitro colony forming cells in developing fetal liver. _J. Cell. Physiol._ 75, 181–192

(1970). Article  CAS  PubMed  Google Scholar  * Dunn, A.R. _et al_. In Biological characterization of regulators encoded by cloned hemopoietic growth factor gene sequences. (Cold Spring

Harbor Laboratory, New York, 1985). * Emanuel, P.O., Bates, L.J., Castleberry, R.B., Gualtieri, R.J. & Zuckerman, K.S. Selective hypersensitivity to granulaocyte-macrophage

colony-stimulating factor by juvenile chronic myeloid leukemia hematopoietic progenitors. _Blood_ 77, 925–929 (1991). CAS  PubMed  Google Scholar  * Miyajima, A., Mui, A.L., Ogorochi, T.

& Sakamaki, K. Receptors for granulocyte-macrophage colony-stimulating factor, interleukin-3, and interleukin-5. _Blood_ 82, 1960–1974 (1993). CAS  PubMed  Google Scholar  *

Castro-Malaspina, H. _et al_.Subacute and chronic myelomonocytic leukemia in children (Juvenile CML): Clinical and hematologic observations, and identification of prognostic factors.

_Cancer_ 54, 675–686 (1984). Article  CAS  PubMed  Google Scholar  * Hestdal, K. _et al_. Characterization and regulation of RB6-8C5 antigen expression on murine bone marrow cells. _J.

Immunol._ 147, 22–28 (1991). CAS  PubMed  Google Scholar  * Lang, R.A. _et al_. Transgenic mice expressing a hemopoietic growth factor gene (GM-CSF) develop accumulations of macrophages,

blindness, and a fatal syndrome of tissue damage. _Cell_ 51, 675–686 (1987). Article  CAS  PubMed  Google Scholar  * Johnson, G.R., Gonda, T.J., Metcalf, D., Hariharan, I.K. & Cory, S. A

lethal myeloproliferative syndrome in mice transplanted with bone marrow cells infected with a retrovirus expressing granulocyte-macrophage colony stimulating factor. _EMBO J._ 8, 441–448

(1989). Article  CAS  PubMed  PubMed Central  Google Scholar  * Satoh, I., Nakafuku, M., Miyajima, A. & Kaziro, Y. Involvement of ras p21 protein in signal-transduction pathways from

interleukin 2, interleukin 3, and granulocyte/macrophage colony-stimulating factor, but not from interleukin 4. _Proc. Natl. Acad. Sci. USA_ 88, 3314–3318 (1991). Article  CAS  PubMed 

PubMed Central  Google Scholar  * DeClue, J.E. _et al_. Abnormal regulation of mammalian p21 ras contrinutes to malignant tumor growth in von Recklinghausen (Type 1)neurofibromatosis. _Cell_

69, 265–273 (1992). Article  CAS  PubMed  Google Scholar  * Basu, T.N. _et al_. Aberrant regulation of ras proteins in malignant tumor cells from type 1 neurofibromatosis patients. _Nature_

356, 713–715 (1992). Article  CAS  PubMed  Google Scholar  * Gonda, T.J., E.M., Macmillan, Townsend, P.V. & Hapel, A.J. Differentiation state and responses to hematopoietic growth

factors of murine myeloid cells transformed by myb. _Blood_ 82, 2813–2822 (1993). CAS  PubMed  Google Scholar  * Gonda, T.J. Molecular and cellular activities of Myb: regulation in normal

hemopoiesis and transformation. _Seminars in virology_ 2, 351–361 (1991). CAS  Google Scholar  * Janssen, J.W.G. _et al_. _RAS_ gene mutations in acute and chronic myelocytic leukemias,

chronic myeloproliferative disorders, and myelodysplastic syndromes. _Proc. Natl. Acad. Sci. USA_ 84, 9228–9232 (1987). Article  CAS  PubMed  PubMed Central  Google Scholar  * The, I. _et

al_. Neurofibromatosis type 1 gene mutations in neuroblastoma. _Nature Genet._ 3, 62–66 (1993). Article  CAS  PubMed  Google Scholar  * Bedigian, H.G., Johnson, D.A., Jenkins, N.A.,

Copeland, N.G. & Evans, R. Spontaneous and induced leukemias of myeloid origin in recombinant inbred BXH–2 mice. _J. Virol._ 51, 586–594 (1984). CAS  PubMed  PubMed Central  Google

Scholar  * Jenkins, N.A., Copeland, N.G., Taylor, B.A., Bedigian, H.G. & Lee, B.K. Ecotropic murine leukemia virus DNA content of normal and lymphomatous tissues of BXH–2 recombinant

inbred mice. _J. Virol._ 42, 379–388 (1982). CAS  PubMed  PubMed Central  Google Scholar  * von Lohuizen, M. & Berns, A. Tumorigenesis by slow transforming retroviruses—an update.

_Biochim. Biophys. Acta._ 1032 (2–3), 213–235 (1990). Google Scholar  * Peters, G. Oncogenes at viral integration sites. _Cell. Growth Differ._ 1, 503–510 (1990). CAS  PubMed  Google Scholar

  * Puil, L. _et al_. Bcr-abl oncoproteins bind directly to activators of the ras signalling pathway. _EMBO J._ 13, 764–773 (1994). Article  CAS  PubMed  PubMed Central  Google Scholar  *

Pendergast, A.M. _et al_. BCR-ABL-induced oncogenesis is mediated by direct interaction of the SH2 domain of the GRB-2 adaptor protein. _Cell_ 75, 175–185 (1993). Article  CAS  PubMed 

Google Scholar  Download references AUTHOR INFORMATION Author notes * Camilynn I. Brannan Present address: Department of Molecular Genetics and Microbiology and Center for Mammalian

Genetics, University of Florida, P.O. Box 100266, Gainesville, Florida, 32610 AUTHORS AND AFFILIATIONS * Mammalian Genetics Laboratory, ABL-Basic Research Program, NCI-Frederick Cancer

Research and Development Center, Frederick, Maryland, 21702 David A. Largaespada, Camilynn I. Brannan, Nancy A. Jenkins & Neal G. Copeland Authors * David A. Largaespada View author

publications You can also search for this author inPubMed Google Scholar * Camilynn I. Brannan View author publications You can also search for this author inPubMed Google Scholar * Nancy A.

Jenkins View author publications You can also search for this author inPubMed Google Scholar * Neal G. Copeland View author publications You can also search for this author inPubMed Google

Scholar RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Largaespada, D., Brannan, C., Jenkins, N. _et al._ _Nf1_ deficiency causes Ras-Dediated

granulocyte/macrophage colony stimulating factor hypersensitivity and chronic myeloid leukaemia. _Nat Genet_ 12, 137–143 (1996). https://doi.org/10.1038/ng0296-137 Download citation *

Received: 10 August 1995 * Accepted: 20 November 1995 * Issue Date: 01 February 1996 * DOI: https://doi.org/10.1038/ng0296-137 SHARE THIS ARTICLE Anyone you share the following link with

will be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt

content-sharing initiative