Skip to main content
SpringerLink
Log in
Book cover

Myeloproliferative Neoplasms pp 3–10Cite as

Update on the Biology of Myeloproliferative Neoplasms

  • Chapter
  • First Online:

  • 1083 Accesses

Part of the book series: Hematologic Malignancies ((HEMATOLOGIC))

Abstract

Single cell origin of hematopoiesis is considered to be a hallmark of all myeloid malignancies. In hematological malignancies, the mutations initiating stem cell clonality can have various forms such as translocated chromosomes, chromosomes with deleted or amplified regions, or point mutations in single genes. Once a stem cell clone has been established, it expands and its progeny competes with healthy cells for “habitat” in the bone marrow microenvironment. As the clone expands, more mutagenesis occurs in the next generation of cells. Although vast majority of these newly acquired genomic mutations do not provide any benefit to the clone, some lesions may prove to be useful and provide a selective advantage. Therefore, selection is the main driving force that shapes the cancer genome in the given environment. Different tissues have different selective forces that evolve the cancer genome. In hematological malignancies, the stem cell clone of each patient takes on a unique evolutionary path even though the accompanying genetic defects are often recurrently detected when many myeloid cancer genomes are compared. The mutations acquired in the evolution of the myeloid cancer genome and their combined effects may have different influence on the differentiation dynamics of the hematopoietic progenitors. Some mutations reduce and others may increase the output of the terminally differentiated cells. Each clonal evolution has a certain phenotypic outcome often detectable by differential blood count and histopathologic evaluation of the bone marrow. The clinical classification of these different phenotypic outcomes provided the foundations for diagnosis in the past. Inclusion of the genetic defects that associate with certain clinical entity into the diagnosis has brought significant improvements in the diagnostic process. The developments in the field of myeloproliferative neoplasms (MPN) in the past decade are an excellent example of this process.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • Abdel-Wahab O, Manshouri T, Patel J, Harris K, Yao J, Hedvat C, Heguy A, Bueso-Ramos C, Kantarjian H, Levine RL et al (2010) Genetic analysis of transforming events that convert chronic myeloproliferative neoplasms to leukemias. Cancer Res 70:447–452

    Article  PubMed  CAS  Google Scholar 

  • Abdel-Wahab O, Pardanani A, Rampal R, Lasho TL, Levine RL, Tefferi A (2011) DNMT3A mutational analysis in primary myelofibrosis, chronic myelomonocytic leukemia and advanced phases of myeloproliferative neoplasms. Leukemia 25(7):1219–1220

    Article  PubMed  CAS  Google Scholar 

  • Andrulis M, Capper D, Meyer J, Penzel R, Hartmann C, Zentgraf H, von Deimling A (2010) IDH1 R132H mutation is a rare event in myeloproliferative neoplasms as determined by a mutation specific antibody. Haematologica 95:1797–1798

    Article  PubMed  Google Scholar 

  • Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, Vassiliou GS, Bench AJ, Boyd EM, Curtin N et al (2005) Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 365:1054–1061

    PubMed  CAS  Google Scholar 

  • Beer PA, Campbell PJ, Scott LM, Bench AJ, Erber WN, Bareford D, Wilkins BS, Reilly JT, Hasselbalch HC, Bowman R et al (2008) MPL mutations in myeloproliferative disorders: analysis of the PT-1 cohort. Blood 112(1):141–149

    Article  PubMed  CAS  Google Scholar 

  • Beer PA, Delhommeau F, LeCouedic JP, Dawson MA, Chen E, Bareford D, Kusec R, McMullin MF, Harrison CN, Vannucchi AM et al (2009) Two routes to leukemic transformation after a JAK2 mutation-positive myeloproliferative neoplasm. Blood 115:2891–2900

    Article  PubMed  Google Scholar 

  • Bjorkholm M, Derolf AR, Hultcrantz M, Kristinsson SY, Ekstrand C, Goldin LR, Andreasson B, Birgegard G, Linder O, Malm C et al (2011) Treatment-related risk factors for transformation to acute myeloid leukemia and myelodysplastic syndromes in myeloproliferative neoplasms. J Clin Oncol 29:2410–2415

    Article  PubMed  Google Scholar 

  • Delhommeau F, Dupont S, Della Valle V, James C, Trannoy S, Masse A, Kosmider O, Le Couedic JP, Robert F, Alberdi A et al (2009) Mutation in TET2 in myeloid cancers. N Engl J Med 360:2289–2301

    Article  PubMed  Google Scholar 

  • Ding Y, Harada Y, Imagawa J, Kimura A, Harada H (2009) AML1/RUNX1 point mutation possibly promotes leukemic transformation in myeloproliferative neoplasms. Blood 114:5201–5205

    Article  PubMed  CAS  Google Scholar 

  • Dunbar AJ, Gondek LP, O’Keefe CL, Makishima H, Rataul MS, Szpurka H, Sekeres MA, Wang XF, McDevitt MA, Maciejewski JP (2008) 250 K single nucleotide polymorphism array karyotyping identifies acquired uniparental disomy and homozygous mutations, including novel missense substitutions of c-Cbl, in myeloid malignancies. Cancer Res 68:10349–10357

    Article  PubMed  CAS  Google Scholar 

  • Ernst T, Chase AJ, Score J, Hidalgo-Curtis CE, Bryant C, Jones AV, Waghorn K, Zoi K, Ross FM, Reiter A et al (2010) Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat Genet 42:722–726

    Article  PubMed  CAS  Google Scholar 

  • Gery S, Cao Q, Gueller S, Xing H, Tefferi A, Koeffler HP (2009) Lnk inhibits myeloproliferative disorder-associated JAK2 mutant, JAK2V617F. J Leukoc Biol 85:957–965

    Article  PubMed  CAS  Google Scholar 

  • Grand FH, Hidalgo-Curtis CE, Ernst T, Zoi K, Zoi C, McGuire C, Kreil S, Jones A, Score J, Metzgeroth G et al (2009) Frequent CBL mutations associated with 11q acquired uniparental disomy in myeloproliferative neoplasms. Blood 113:6182–6192

    Article  PubMed  CAS  Google Scholar 

  • Green A, Beer P (2010) Somatic mutations of IDH1 and IDH2 in the leukemic transformation of myeloproliferative neoplasms. N Engl J Med 362:369–370

    Article  PubMed  CAS  Google Scholar 

  • Harutyunyan A, Gisslinger B, Klampfl T, Berg T, Bagienski K, Gisslinger H, Kralovics R (2011a) Rare germline variants in regions of loss of heterozygosity may influence clinical course of hematological malignancies. Leukemia 12:1782–1784

    Google Scholar 

  • Harutyunyan A, Klampfl T, Cazzola M, Kralovics R (2011b) p53 lesions in leukemic transformation. N Engl J Med 364:488–490

    Article  PubMed  CAS  Google Scholar 

  • Jager R, Gisslinger H, Passamonti F, Rumi E, Berg T, Gisslinger B, Pietra D, Harutyunyan A, Klampfl T, Olcaydu D et al (2010) Deletions of the transcription factor Ikaros in myeloproliferative neoplasms. Leukemia 24:1290–1298

    Article  PubMed  CAS  Google Scholar 

  • James C, Ugo V, Le Couedic JP, Staerk J, Delhommeau F, Lacout C, Garcon L, Raslova H, Berger R, Bennaceur-Griscelli A et al (2005) A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 434:1144–1148

    Article  PubMed  CAS  Google Scholar 

  • Jones AV, Chase A, Silver RT, Oscier D, Zoi K, Wang YL, Cario H, Pahl HL, Collins A, Reiter A et al (2009) JAK2 haplotype is a major risk factor for the development of myeloproliferative neoplasms. Nat Genet 41:446–449

    Article  PubMed  CAS  Google Scholar 

  • Jost E, do ON, Dahl E, Maintz CE, Jousten P, Habets L, Wilop S, Herman JG, Osieka R, Galm O (2007) Epigenetic alterations complement mutation of JAK2 tyrosine kinase in patients with BCR/ABL-negative myeloproliferative disorders. Leukemia 21:505–510

    Article  PubMed  CAS  Google Scholar 

  • Kilpivaara O, Mukherjee S, Schram AM, Wadleigh M, Mullally A, Ebert BL, Bass A, Marubayashi S, Heguy A, Garcia-Manero G et al (2009) A germline JAK2 SNP is associated with predisposition to the development of JAK2(V617F)-positive myeloproliferative neoplasms. Nat Genet 41:455–459

    Article  PubMed  CAS  Google Scholar 

  • Klampfl T, Harutyunyan A, Berg T, Gisslinger B, Schalling M, Bagienski K, Olcaydu D, Passamonti F, Rumi E, Pietra D et al (2011) Genome integrity of myeloproliferative neoplasms in chronic phase and during disease progression. Blood 118:167–176

    Article  PubMed  CAS  Google Scholar 

  • Kosmider O, Gelsi-Boyer V, Slama L, Dreyfus F, Beyne-Rauzy O, Quesnel B, Hunault-Berger M, Slama B, Vey N, Lacombe C et al (2010) Mutations of IDH1 and IDH2 genes in early and accelerated phases of myelodysplastic syndromes and MDS/myeloproliferative neoplasms. Leukemia 24:1094–1096

    Article  PubMed  CAS  Google Scholar 

  • Kralovics R (2008) Genetic complexity of myeloproliferative neoplasms. Leukemia 22:1841–1848

    Article  PubMed  CAS  Google Scholar 

  • Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, Tichelli A, Cazzola M, Skoda RC (2005) A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 352:1779–1790

    Article  PubMed  CAS  Google Scholar 

  • Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ, Boggon TJ, Wlodarska I, Clark JJ, Moore S et al (2005) Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 7:387–397

    Article  PubMed  CAS  Google Scholar 

  • Lin P, Jones D, Medeiros LJ, Chen W, Vega-Vazquez F, Luthra R (2006) Activating FLT3 mutations are detectable in chronic and blast phase of chronic myeloproliferative disorders other than chronic myeloid leukemia. Am J Clin Pathol 126:530–533

    Article  PubMed  CAS  Google Scholar 

  • Nicola NA, Nicholson SE, Metcalf D, Zhang JG, Baca M, Farley A, Willson TA, Starr R, Alexander W, Hilton DJ (1999) Negative regulation of cytokine signaling by the SOCS proteins. Cold Spring Harb Symp Quant Biol 64:397–404

    Article  PubMed  CAS  Google Scholar 

  • Ogawa S, Sanada M, Shih LY, Suzuki T, Otsu M, Nakauchi H, Koeffler HP (2010a) Gain-of-function c-CBL mutations associated with uniparental disomy of 11q in myeloid neoplasms. Cell Cycle 9:1051–1056

    Article  PubMed  CAS  Google Scholar 

  • Ogawa S, Shih LY, Suzuki T, Otsu M, Nakauchi H, Koeffler HP, Sanada M (2010b) Deregulated intracellular signaling by mutated c-CBL in myeloid neoplasms. Clin Cancer Res 16:3825–3831

    Article  PubMed  CAS  Google Scholar 

  • Oh ST, Simonds EF, Jones C, Hale MB, Goltsev Y, Gibbs KD Jr, Merker JD, Zehnder JL, Nolan GP, Gotlib J (2010) Novel mutations in the inhibitory adaptor protein LNK drive JAK-STAT signaling in patients with myeloproliferative neoplasms. Blood 116:988–992

    Article  PubMed  CAS  Google Scholar 

  • Oki Y, Jelinek J, Beran M, Verstovsek S, Kantarjian HM, Issa JP (2006) Mutations and promoter methylation status of NPM1 in myeloproliferative disorders. Haematologica 91:1147–1148

    PubMed  CAS  Google Scholar 

  • Olcaydu D, Harutyunyan A, Jager R, Berg T, Gisslinger B, Pabinger I, Gisslinger H, Kralovics R (2009a) A common JAK2 haplotype confers susceptibility to myeloproliferative neoplasms. Nat Genet 41:450–454

    Article  PubMed  CAS  Google Scholar 

  • Olcaydu D, Skoda RC, Looser R, Li S, Cazzola M, Pietra D, Passamonti F, Lippert E, Carillo S, Girodon F et al (2009b) The ‘GGCC’ haplotype of JAK2 confers susceptibility to JAK2 exon 12 mutation-positive polycythemia vera. Leukemia 23(10):1924–1926

    Article  PubMed  CAS  Google Scholar 

  • Olcaydu D, Rumi E, Harutyunyan A, Passamonti F, Pietra D, Pascutto C, Berg T, Jager R, Hammond E, Cazzola M et al (2011) The role of the JAK2 GGCC haplotype and the TET2 gene in familial myeloproliferative neoplasms. Haematologica 96:367–374

    Article  PubMed  Google Scholar 

  • Pardanani AD, Levine RL, Lasho T, Pikman Y, Mesa RA, Wadleigh M, Steensma DP, Elliott MA, Wolanskyj AP, Hogan WJ et al (2006) MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. Blood 108:3472–3476

    Article  PubMed  CAS  Google Scholar 

  • Pardanani A, Lasho T, Finke C, Oh ST, Gotlib J, Tefferi A (2010a) LNK mutation studies in blast-phase myeloproliferative neoplasms, and in chronic-phase disease with TET2, IDH, JAK2 or MPL mutations. Leukemia 24:1713–1718

    Article  PubMed  CAS  Google Scholar 

  • Pardanani A, Lasho TL, Finke CM, Mai M, McClure RF, Tefferi A (2010b) IDH1 and IDH2 mutation analysis in chronic- and blast-phase myeloproliferative neoplasms. Leukemia 24:1146–1151

    Article  PubMed  CAS  Google Scholar 

  • Pikman Y, Lee BH, Mercher T, McDowell E, Ebert BL, Gozo M, Cuker A, Wernig G, Moore S, Galinsky I et al (2006) MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med 3:e270

    Article  PubMed  Google Scholar 

  • Sanada M, Suzuki T, Shih LY, Otsu M, Kato M, Yamazaki S, Tamura A, Honda H, Sakata-Yanagimoto M, Kumano K et al (2009) Gain-of-function of mutated C-CBL tumour suppressor in myeloid neoplasms. Nature 460:904–908

    Article  PubMed  CAS  Google Scholar 

  • Schmidt MH, Dikic I (2005) The Cbl interactome and its functions. Nat Rev Mol Cell Biol 6:907–918

    Article  PubMed  CAS  Google Scholar 

  • Schnittger S, Bacher U, Haferlach C, Alpermann T, Dicker F, Sundermann J, Kern W, Haferlach T (2011) Characterization of NPM1-mutated AML with a history of myelodysplastic syndromes or myeloproliferative neoplasms. Leukemia 25:615–621

    Article  PubMed  CAS  Google Scholar 

  • Simon C, Dondi E, Chaix A, de Sepulveda P, Kubiseski TJ, Varin-Blank N, Velazquez L (2008) Lnk adaptor protein down-regulates specific Kit-induced signaling pathways in primary mast cells. Blood 112:4039–4047

    Article  PubMed  CAS  Google Scholar 

  • Stegelmann F, Bullinger L, Griesshammer M, Holzmann K, Habdank M, Kuhn S, Maile C, Schauer S, Dohner H, Dohner K (2010) High-resolution single-nucleotide polymorphism array-profiling in myeloproliferative neoplasms identifies novel genomic aberrations. Haematologica 95:666–669

    Article  PubMed  CAS  Google Scholar 

  • Stegelmann F, Bullinger L, Schlenk RF, Paschka P, Griesshammer M, Blersch C, Kuhn S, Schauer S, Dohner H, Dohner K (2011) DNMT3A mutations in myeloproliferative neoplasms. Leukemia 25(7):1217–1219

    Article  PubMed  CAS  Google Scholar 

  • Taketani T, Taki T, Takita J, Ono R, Horikoshi Y, Kaneko Y, Sako M, Hanada R, Hongo T, Hayashi Y (2002) Mutation of the AML1/RUNX1 gene in a transient myeloproliferative disorder patient with Down syndrome. Leukemia 16:1866–1867

    Article  PubMed  CAS  Google Scholar 

  • Tefferi A (2010) Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1. Leukemia 24:1128–1138

    Article  PubMed  CAS  Google Scholar 

  • Tefferi A, Lim KH, Abdel-Wahab O, Lasho TL, Patel J, Patnaik MM, Hanson CA, Pardanani A, Gilliland DG, Levine RL (2009a) Detection of mutant TET2 in myeloid malignancies other than myeloproliferative neoplasms: CMML, MDS, MDS/MPN and AML. Leukemia 23:1343–1345

    Article  PubMed  CAS  Google Scholar 

  • Tefferi A, Pardanani A, Lim KH, Abdel-Wahab O, Lasho TL, Patel J, Gangat N, Finke CM, Schwager S, Mullally A et al (2009b) TET2 mutations and their clinical correlates in polycythemia vera, essential thrombocythemia and myelofibrosis. Leukemia 23(5):905–911

    Article  PubMed  CAS  Google Scholar 

  • Teofili L, Martini M, Cenci T, Guidi F, Torti L, Giona F, Foa R, Leone G, Larocca LM (2008) Epigenetic alteration of SOCS family members is a possible pathogenetic mechanism in JAK2 wild type myeloproliferative diseases. Int J Cancer 123:1586–1592

    Article  PubMed  CAS  Google Scholar 

  • Thoennissen NH, Krug UO, Lee DH, Kawamata N, Iwanski GB, Lasho T, Weiss T, Nowak D, Koren-Michowitz M, Kato M et al (2010) Prevalence and prognostic impact of allelic imbalances associated with leukemic transformation of Philadelphia chromosome-negative myeloproliferative neoplasms. Blood 115:2882–2890

    Article  PubMed  CAS  Google Scholar 

  • Tong W, Lodish HF (2004) Lnk inhibits Tpo-mpl signaling and Tpo-mediated megakaryocytopoiesis. J Exp Med 200:569–580

    Article  PubMed  Google Scholar 

  • Tong W, Zhang J, Lodish HF (2005) Lnk inhibits erythropoiesis and Epo-dependent JAK2 activation and downstream signaling pathways. Blood 105:4604–4612

    Article  PubMed  CAS  Google Scholar 

  • Vannucchi AM, Antonioli E, Guglielmelli P, Rambaldi A, Barosi G, Marchioli R, Marfisi RM, Finazzi G, Guerini V, Fabris F et al (2007) Clinical profile of homozygous JAK2 617V>F mutation in patients with polycythemia vera or essential thrombocythemia. Blood 110:840–846

    Article  PubMed  CAS  Google Scholar 

  • Veerakumarasivam A, Scott HE, Chin SF, Warren A, Wallard MJ, Grimmer D, Ichimura K, Caldas C, Collins VP, Neal DE et al (2008) High-resolution array-based comparative genomic hybridization of bladder cancers identifies mouse double minute 4 (MDM4) as an amplification target exclusive of MDM2 and TP53. Clin Cancer Res 14:2527–2534

    Article  PubMed  CAS  Google Scholar 

  • Velazquez L, Cheng AM, Fleming HE, Furlonger C, Vesely S, Bernstein A, Paige CJ, Pawson T (2002) Cytokine signaling and hematopoietic homeostasis are disrupted in Lnk-deficient mice. J Exp Med 195:1599–1611

    Article  PubMed  CAS  Google Scholar 

  • Wattel E, Preudhomme C, Hecquet B, Vanrumbeke M, Quesnel B, Dervite I, Morel P, Fenaux P (1994) p53 mutations are associated with resistance to chemotherapy and short survival in hematologic malignancies. Blood 84:3148–3157

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Center for Molecular Medicine (CeMM) of the Austrian Academy of Sciences, Vienna, Austria

    Robert Kralovics

  2. Division of Hematology and Blood Coagulation, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria

    Robert Kralovics

Authors
  1. Robert Kralovics
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert Kralovics .

Editor information

Editors and Affiliations

  1. Div. Ematologia, Ospedali Riuniti di Bergamo, Largo Barozzi 1, Bergamo, 24128, Italy

    Tiziano Barbui

  2. Dept. Internal Medicine, Div. Hematology, Mayo Clinic, First Street SW. 200, Rochester, 55905, Minnesota, USA

    Ayalew Tefferi

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Kralovics, R. (2012). Update on the Biology of Myeloproliferative Neoplasms. In: Barbui, T., Tefferi, A. (eds) Myeloproliferative Neoplasms. Hematologic Malignancies. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-24989-1_1

Download citation

  • DOI: https://doi.org/10.1007/978-3-642-24989-1_1

  • Published:

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-24988-4

  • Online ISBN: 978-3-642-24989-1

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation