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Familial Myeloproliferative Disorders

Written2015-09Christine Bellanné-Chantelot, Isabelle Plo
Département de Génétique, Hôpitaux Universitaires Pitié-Salpétrière-Charles Foix, Paris (CBC); INSERM UMR1170, Institut Gustave Roussy, Villejuif (CBC, IP), France;
Abstract Review on Familial Myeloproliferative Disorders, with data on clinics, and the genes involved.

Keyword Familial; Myeloproliferative disorders; Hereditary erythrocytosis; Hereditary thrombocytosis; TERT; GSKIP; ATG2B; RBBP6

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Other namesFamilial myeloproliferative neoplasms
Hereditary erythrocytosis
Hereditary thrombocytosis
Atlas_Id 10180
Note Myeloproliferative neoplasms (MPN) are clonal and chronic hematological malignancies caused by genetic defects that result in overproduction of one or several myeloid lineages (erythroïd, megakaryocytic and granulocytic lineages). The classic MPN or Ph-chromosome-negative MPN include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF).
Familial MPN are estimated to 2 to 10% according to studies.
They are divided in two overlapping entities:
- True MPN disorders with germline predisposition that are familial clustering of MPN with autosomal dominant inheritance and incomplete penetrance. These familial cases are indistinguishable from the sporadic cases of MPN in terms of clinical features and acquired genetic abnormalities.
- Hereditary MPN-like disorders with clinical symptoms of MPN but affecting a single lineage involvement. They include hereditary thrombocytosis ( THPO, MPL, JAK2 genes), hereditary erythrocytosis ( EPOR, VHL, EGLN1 and EPAS1 genes) and hereditary neutrophilia ( gene). These hereditary disorders are non-malignant diseases and have distinct features: polyclonal hematopoiesis, absence of disease progression and autosomal dominant inheritance with complete penetrance.
Inheritance Most of familial MPN are compatible with an autosomal dominant with incomplete penetrance. However, an autosomal recessive pattern has been suggested by some authors and could not be excluded.


Phenotype and clinics Familial MPN include the three classic MPN or Ph-chromosome-negative MPN: PV, ET, and PMF. Patients with familial MPN have the same clinical presentation at diagnosis as patients with sporadic MPN. They develop the same type of complications (thrombosis and hemorrhage) and disease evolution (post-PV myelofibrosis, post-ET myelofibrosis, and acute myeloid leukemia). The distribution of MPN phenotypes within MPN families is homogeneous in half of cases (all affected family cases have the same MPN).
Neoplastic risk RISK increased of transformation to acute myeloid leukemia (AML)
Treatment The recommendations are those used for sporadic MPNS. In low-risk patients, phlebotomy in PV patients and low-dose aspirin in ET patients are recommended. In the presence of risk factors for thrombosis, hydroxyurea is used as first-line treatment and busulfan or interferon-α as second-line. Novel therapies based on JAK2 inhibitors have been developed and up to date, are restricted to patients with myelofibrosis.
Evolution The main cause of death is the evolution to myelofibrosis and AML. In familial cases, the incidence annual rate of AML has been estimated to 1.25% patients/year for PV and 0.68% patients/year for ET.
Prognosis Familial PV: 83% of overall survival at 10 years; Familial ET: 84% to 100% of overall survival at 10 years; Familial PMF: 30% of overall survival at 10 years.


Cytogenetics of cancer Chromosomal aberrations observed in familial MPN are similar to those reported in sporadic cases. About two-third of MPN harbor at least one chromosomal aberration. Some of them are more specifically acquired with disease progression to secondary myelofibrosis such as uniparental disomy (UPD) of 9p, gain of 1q whereas others are more frequently associated with post-MPN acute myeloid leukemia such as gain of 1q, deletions of 7q, 5q, 6p, 7p, 3q and UPD of 19q and 22q.

Other findings

Note MPNs are driven by at least one somatic acquired mutation (V617F in JAK2 or mutations in MPL and CALR for ET and PMF) and mutations in epigenetic regulators such as TET2, IDH1, IDH2 and . Familial MPNs harbor the same acquired somatic profile as sporadic MPN cases.
Several predisposing single-nucleotide polymorphism (SNP) such as the JAK2 haplotype 46/1 (also named GGCC) in JAK2, SNP rs2736100 in TERT, SNP rs2201862 in MECOM and SNP rs9376092 in HBS1L / MYB have been shown to play a role in the development of MPN in the general population by favoring the acquisition of driver mutations. However, except TERT (detailed below, none of them explain the familial clustering of MPN.

Genes involved and Proteins

Gene NameRBBP6 (RB binding protein 6, ubiquitin ligase)
Location 16p12.1
Transcription NM_006910.4 encodes the longest transcript.
Description Protein of 1792 amino acids.
Function Possible link to P53 function.
Germinal All mutations located in the putative p53-binding region.

Gene NameATG2B (Autophagy-related 2B)
Location 14q32.2
Note Cooperates with GSKIP, also located in 14q32.2 and included in the 700 kb duplication NC_000014.9:g.95696766_96390792dup (on Assembly GRCh38).
Transcription Unique transcript NM_018036.
Description Protein of 2078 amino acids.
Expression Expressed in CD34+ hematopoietic progenitors and during erythroïd and megakaryocyte differentiation.
Function Overexpression of ATG2B enhances hematopoietic progenitor differentiation, particularly in megacaryocytes and cooperates with classical driver mutations.
Note Founder defect in families originated from West-Indies.
Germinal Head-to-tail 700 kb tandem duplication (g.95696766_96390792dup).
Somatic Associated with classical driver mutations such as V617F in JAK2, W515L in MPL and 1099_1050del52 in CALR and with an increased frequency of mutations in TET2, IDH1 and IDH2.

Gene NameGSKIP (GSK3-beta interaction protein)
Alias C14orf129
Location 14q32.2
Note Cooperates with ATG2B, also located in 14q32.2 and included in the 700 kb duplication NC_000014.9:g.95696766_96390792dup (on Assembly GRCh38).
Transcription NM_001271904 encodes the longest transcript; 3 other transcripts encode the same protein with differences in the 5'UTR.
Description Protein of 139 amino acids.
Expression in CD34+ hematopoietic progenitors and during erythroïd and megakaryocyte differentiation.
Function Overexpression of GSKIP enhances hematopoietic progenitor differentiation, particularly of megacaryocytes and cooperates with classical driver mutations.
Note Founder defect in families originated from West-Indies.
Germinal Head-to-tail 700 kb tandem duplication (g.95696766_96390792dup).
Somatic Associated with classical driver mutations such as V617F in JAK2, W515L in MPL and 1099_1050del52 in CALR and with an increased frequency of mutations in TET2, IDH1 and IDH2.

Gene NameTERT (telomerase reverse transcriptase)
Location 5p15.33
Transcription NM_198253.2 encodes the longest isoform (1); a shorter isoform lacking an alternate in-frame exon in the middle portion of the coding exon is also reported.
Description Protein of 1132 amino acids.
Expression Blood cells.
Function Telomerase activity, essential for maintaining telomere length.
Germinal Allele C of SNP rs2736100, located in the second intron of the TERT gene, is associated with an increased risk for MPN (PV, ET and PMF).

To be noted

Germline duplication of ATG2B and GSKIP predispose with a high penetrance (above 80%) to several myeloid malignancies, particularly essential thrombocythemia frequently progressing to AML.
RBBP6 germline gain-of-function mutations mostly associated with primary myelofibrosis, observed in 5% of the familial and 0.6% of the sporadic MPN cases.
TERT rs2736100_C risk allele is significantly associated with familial MPN, whatever the subtype (PV, ET and PMF


Genetic and clinical implications of the Val617Phe JAK2 mutation in 72 families with myeloproliferative disorders
Bellanné-Chantelot C, Chaumarel I, Labopin M, Bellanger F, Barbu V, De Toma C, Delhommeau F, Casadevall N, Vainchenker W, Thomas G, Najman A
Blood 2006 Jul 1;108(1):346-52
PMID 16537803
Mutation in TET2 in myeloid cancers
Delhommeau F, Dupont S, Della Valle V, James C, Trannoy S, Massé A, Kosmider O, Le Couedic JP, Robert F, Alberdi A, Lécluse Y, Plo I, Dreyfus FJ, Marzac C, Casadevall N, Lacombe C, Romana SP, Dessen P, Soulier J, Viguié F, Fontenay M, Vainchenker W, Bernard OA
N Engl J Med 2009 May 28;360(22):2289-301
PMID 19474426
Role of germline genetic factors in MPN pathogenesis
Harutyunyan AS, Kralovics R
Hematol Oncol Clin North Am 2012 Oct;26(5):1037-51
PMID 23009936
Germline RBBP6 Mutations In Myeloproliferative Neoplasms.
Harutyunyan, AS, Giambruno R, Christian Krendl K, Stukalov A, Klampfl T, Berg T, Milosevic, JD, Chen D, Gisslinger B, Gisslinger H, Rumi E, Passamonti F, Pietra D, Mueller A, Parapatics K, Breitwieser FP, Herrmann R, Colinge J, Bennett KL, Superti-Furga G, Cazzola M, Hammond E and Kralovics R.
55th ASH Annual Meeting and Exposition. Abstract 267. New Orleans, LA, 2013.
Common germline variation at the TERT locus contributes to familial clustering of myeloproliferative neoplasms
Jäger R, Harutyunyan AS, Rumi E, Pietra D, Berg T, Olcaydu D, Houlston RS, Cazzola M, Kralovics R
Am J Hematol 2014 Dec;89(12):1107-10
PMID 25196853
JAK2 haplotype is a major risk factor for the development of myeloproliferative neoplasms
Jones AV, Chase A, Silver RT, Oscier D, Zoi K, Wang YL, Cario H, Pahl HL, Collins A, Reiter A, Grand F, Cross NC
Nat Genet 2009 Apr;41(4):446-9
PMID 19287382
Inherited predisposition to myeloproliferative neoplasms
Jones AV, Cross NC
Ther Adv Hematol 2013 Aug;4(4):237-53
PMID 23926457
Somatic mutations of calreticulin in myeloproliferative neoplasms
Klampfl T, Gisslinger H, Harutyunyan AS, Nivarthi H, Rumi E, Milosevic JD, Them NC, Berg T, Gisslinger B, Pietra D, Chen D, Vladimer GI, Bagienski K, Milanesi C, Casetti IC, Sant'Antonio E, Ferretti V, Elena C, Schischlik F, Cleary C, Six M, Schalling M, Schönegger A, Bock C, Malcovati L, Pascutto C, Superti-Furga G, Cazzola M, Kralovics R
N Engl J Med 2013 Dec 19;369(25):2379-90
PMID 24325356
Genome integrity of myeloproliferative neoplasms in chronic phase and during disease progression
Klampfl T, Harutyunyan A, Berg T, Gisslinger B, Schalling M, Bagienski K, Olcaydu D, Passamonti F, Rumi E, Pietra D, Jäger R, Pieri L, Guglielmelli P, Iacobucci I, Martinelli G, Cazzola M, Vannucchi AM, Gisslinger H, Kralovics R
Blood 2011 Jul 7;118(1):167-76
PMID 21531982
Genetic complexity of myeloproliferative neoplasms
Kralovics R
Leukemia 2008 Oct;22(10):1841-8
PMID 18754034
A common JAK2 haplotype confers susceptibility to myeloproliferative neoplasms
Olcaydu D, Harutyunyan A, Jäger R, Berg T, Gisslinger B, Pabinger I, Gisslinger H, Kralovics R
Nat Genet 2009 Apr;41(4):450-4
PMID 19287385
The role of the JAK2 GGCC haplotype and the TET2 gene in familial myeloproliferative neoplasms
Olcaydu D, Rumi E, Harutyunyan A, Passamonti F, Pietra D, Pascutto C, Berg T, Jäger R, Hammond E, Cazzola M, Kralovics R
Haematologica 2011 Mar;96(3):367-74
PMID 21173100
Myeloproliferative neoplasms: JAK2 signaling pathway as a central target for therapy
Pasquier F, Cabagnols X, Secardin L, Plo I, Vainchenker W
Clin Lymphoma Myeloma Leuk 2014 Sep;14 Suppl:S23-35
PMID 25486952
CALR exon 9 mutations are somatically acquired events in familial cases of essential thrombocythemia or primary myelofibrosis
Rumi E, Harutyunyan AS, Pietra D, Milosevic JD, Casetti IC, Bellini M, Them NC, Cavalloni C, Ferretti VV, Milanesi C, Berg T, Sant'Antonio E, Boveri E, Pascutto C, Astori C, Kralovics R, Cazzola M; Associazione Italiana per la Ricerca sul Cancro Gruppo Italiano Malattie Mieloproliferative Investigators
Blood 2014 Apr 10;123(15):2416-9
PMID 24553179
Analysis of the ten-eleven translocation 2 (TET2) gene in familial myeloproliferative neoplasms
Saint-Martin C, Leroy G, Delhommeau F, Panelatti G, Dupont S, James C, Plo I, Bordessoule D, Chomienne C, Delannoy A, Devidas A, Gardembas-Pain M, Isnard F, Plumelle Y, Bernard O, Vainchenker W, Najman A, Bellanné-Chantelot C; French Group of Familial Myeloproliferative Disorders
Blood 2009 Aug 20;114(8):1628-32
PMID 19564637
Germline duplication of ATG2B and GSKIP predisposes to familial myeloid malignancies
Saliba J, Saint-Martin C, Di Stefano A, Lenglet G, Marty C, Keren B, Pasquier F, Valle VD, Secardin L, Leroy G, Mahfoudhi E, Grosjean S, Droin N, Diop M, Dessen P, Charrier S, Palazzo A, Merlevede J, Meniane JC, Delaunay-Darivon C, Fuseau P, Isnard F, Casadevall N, Solary E, Debili N, Bernard OA, Raslova H, Najman A, Vainchenker W, Bellanné-Chantelot C, Plo I
Nat Genet 2015 Oct;47(10):1131-40
PMID 26280900
New and treatment-relevant risk stratification for thrombosis in essential thrombocythemia and polycythemia vera
Tefferi A, Barbui T
Am J Hematol 2015 Aug;90(8):683-5
PMID 25872987
New mutations and pathogenesis of myeloproliferative neoplasms
Vainchenker W, Delhommeau F, Constantinescu SN, Bernard OA
Blood 2011 Aug 18;118(7):1723-35
PMID 21653328


This paper should be referenced as such :
Christine Bellann-Chantelot, Isabelle Plo
Familial Myeloproliferative Disorders
Atlas Genet Cytogenet Oncol Haematol. 2016;20(9):502-505.
Free journal version : [ pdf ]   [ DOI ]
On line version :

Other genes implicated (Data extracted from papers in the Atlas) [ 4 ]


External links

Other databaseClinVar : SCV000224007-4010
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