Acquisition of jak2, ptpn11, and ras mutations during disease progression in primary myelodysplastic syndrome

Access through your institution Buy or subscribe Cytokines play an important role in the developmental programs of normal hematopoiesis and leukemia. Signaling through cytokines receptors is

mediated in part by the activation of tyrosine kinases, particularly the Janus kinases (_Jaks_). Many of the effects of _Jak2_ are mediated through the recruitment of signal transducer and

activator of transcription (_Stat_) to phosphotyrosyl residues on the erythropoietin, granulocyte macrophage colony-stimulating factor, and interleukin-3 receptors. _Shp2_, the nonreceptor

tyrosine phosphatase encoded by _PTPN11_, also participates in signaling events downstream of the receptors of growth factors, cytokines, hormones, antigens, and extracellular matrixes. It

has compound functions and is involved in a variety of signal transduction processes, such as the _Ras-Raf-Map_ kinase, _Jak-Stat, PI3_ kinase, and nuclear factor-_κB_ (_NF-κB_) pathways.

_Jak2_ and _Shp2_ form a complex signaling network in hematopoietic progenitor cells. Perturbed _Jak2_ and _Shp2_ signalings may induce hematopoietic malignancies. Recently, a somatic point

mutation of _JAK2_ (V617F), which results in constitutive activation of the tyrosine kinase and factor independent growth of hematopoietic cells, has been found in patients with

myeloproliferative disorders.1 Dominant mutations in _PTPN11_, which result in gain of function of _shp2_, have also been demonstrated in juvenile myelomonocytic leukemia (JMML).2

Myelodysplastic syndrome (MDS) is a clonal disease usually characterized by hypercellular marrow with features of ineffective and dysplastic hematopoiesis, which can lead to fatal cytopenia

or leukemic transformation. The mechanisms underlying the development of MDS and its progression to acute leukemia remain unclear. Activating mutations in _N-RAS_ and _K-RAS_, which

upregulate downstream signaling pathways, are frequently observed in MDS, and have been implicated in poor prognosis and increased risk of leukemia.3 Studies on the genetic mutations of

_JAK2_ and _PTPN11_ in MDS remain limited and there has been no report of simultaneous sequential study of both genes during clinical follow-up. In this study, we analyzed the mutations of

_JAK2, PTPN11_, and _RAS_ in patients with primary MDS and patients with JMML. Serial studies were performed during the follow-up period to assess the acquisition of mutations during disease

progression. 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 $259.00 per year only $21.58 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 REFERENCES * Baxter EJ, Scott

LM, Campbell PJ, East C, Fourouclas N, Swanton S _et al_. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. _Lancet_ 2005; 365: 1054–1061. Article  CAS 

Google Scholar  * Tartaglia M, Niemeyer CM, Fragale A, Song X, Buechner J, Jung A _et al_. Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and

acute myeloid leukemia. _Nat Genet_ 2003; 34: 148–150. Article  CAS  Google Scholar  * Padua RA, Guinn BA, Al-Sabah AI, Smith M, Taylor C, Pettersson T _et al_. RAS, FMS and p53 mutations

and poor clinical outcome in myelodysplasias: a ten-year follow-up. _Leukemia_ 1998; 12: 887–892. Article  CAS  Google Scholar  * Hugues L, Cave H, Philippe N, Pereira S, Fenaux P,

Preudhomme C . Mutations of PTPN11 are rare in adult myeloid malignancies. _Haematologica_ 2005; 90: 853–854. PubMed  Google Scholar  * Johan MF, Bowen DT, Frew ME, Goodeve AC, Wilson GA,

Peake IR _et al_. Mutations in PTPN11 are uncommon in adult myelodysplastic syndromes and acute myeloid leukaemia. _Br J Haematol_ 2004; 124: 843–844. Article  CAS  Google Scholar  *

Steensma DP, Dewald GW, Lasho TL, Powell HL, McClure RF, Levine RL _et al_. The JAK2 V617F Activating Tyrosine Kinase Mutation is an Infrequent Event in Both ‘Atypical’ Myeloproliferative

Disorders and the Myelodysplastic Syndrome. _Blood_ 2005; 106: 1207–1209. Article  CAS  Google Scholar  * Levine RL, Loriaux M, Huntly BJ, Loh ML, Beran M, Stoffregen E _et al_. The

JAK2V617F activating mutation occurs in chronic myelomonocytic leukemia and acute myeloid leukemia, but not in acute lymphoblastic leukemia or chronic lymphocytic leukemia. _Blood_ 2005;

106: 3377–3379. Article  CAS  Google Scholar  * Tartaglia M, Niemeyer CM, Shannon KM, Loh ML . SHP-2 and myeloid malignancies. _Curr Opin Hematol_ 2004; 11: 44–50. Article  CAS  Google

Scholar  * Yin T, Shen R, Feng GS, Yang YC . Molecular Characterization of Specific Interactions between SHP-2 Phosphatase and JAK Tyrosine Kinases. _J Biol Chem_ 1997; 272: 1032–1037.

Article  CAS  Google Scholar  Download references ACKNOWLEDGEMENTS This work was supported in part by grants from the National Science Council of the Republic of China NSC 93-2314-B002-038

and NSC 94-2752-B002-006-PAE, National Taiwan University Hospital NTUH 93-5051 and the Department of Medical Research in National Taiwan University Hospital, Taiwan. AUTHOR INFORMATION

AUTHORS AND AFFILIATIONS * Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan C-Y Chen, J-L Tang, W Tsay, Y-C Yeh, C-F Huang, R-J Chiou, M Yao, 

B-S Ko, Y-C Chen & H-F Tien * Department of Laboratory Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan L-I Lin, Y-C Chen & D-T Lin * Department of Clinical

Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan L-I Lin * Department of Pediatrics, College of Medicine, National Taiwan

University, Taipei, Taiwan H-H Chang, K-H Lin & D-T Lin Authors * C-Y Chen View author publications You can also search for this author inPubMed Google Scholar * L-I Lin View author

publications You can also search for this author inPubMed Google Scholar * J-L Tang View author publications You can also search for this author inPubMed Google Scholar * W Tsay View author

publications You can also search for this author inPubMed Google Scholar * H-H Chang View author publications You can also search for this author inPubMed Google Scholar * Y-C Yeh View

author publications You can also search for this author inPubMed Google Scholar * C-F Huang View author publications You can also search for this author inPubMed Google Scholar * R-J Chiou

View author publications You can also search for this author inPubMed Google Scholar * M Yao View author publications You can also search for this author inPubMed Google Scholar * B-S Ko

View author publications You can also search for this author inPubMed Google Scholar * Y-C Chen View author publications You can also search for this author inPubMed Google Scholar * K-H Lin

View author publications You can also search for this author inPubMed Google Scholar * D-T Lin View author publications You can also search for this author inPubMed Google Scholar * H-F

Tien View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to H-F Tien. RIGHTS AND PERMISSIONS Reprints and permissions

ABOUT THIS ARTICLE CITE THIS ARTICLE Chen, CY., Lin, LI., Tang, JL. _et al._ Acquisition of _JAK2_, _PTPN11_, and _RAS_ mutations during disease progression in primary myelodysplastic

syndrome. _Leukemia_ 20, 1155–1158 (2006). https://doi.org/10.1038/sj.leu.2404190 Download citation * Published: 06 April 2006 * Issue Date: 01 June 2006 * DOI:

https://doi.org/10.1038/sj.leu.2404190 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