Familial Myeloproliferative Disorders

Familial myeloproliferative neoplasms , Hereditary erythrocytosis , Hereditary thrombocytosis

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 (CSF3R 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.

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.

187950 , 254450 , 601626

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).

RISK increased of transformation to acute myeloid leukemia (AML)

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.

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.

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.

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.

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

Encoded in 18 exons spanning 33.2 Kb.

NM_006910.4 encodes the longest transcript.

Protein of 1792 amino acids.

Possible link to P53 function.

All mutations located in the putative p53-binding region.

Cooperates with GSKIP, also located in 14q32.2 and included in the 700 kb duplication NC_000014.9:g.95696766_96390792dup (on Assembly GRCh38).

Encoded in 42 exons spanning 82 Kb.

Unique transcript NM_018036.

Protein of 2078 amino acids.

Expressed in CD34+ hematopoietic progenitors and during erythroïd and megakaryocyte differentiation.

Overexpression of ATG2B enhances hematopoietic progenitor differentiation, particularly in megacaryocytes and cooperates with classical driver mutations.

Founder defect in families originated from West-Indies.

Head-to-tail 700 kb tandem duplication (g.95696766_96390792dup).

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.

C14orf129

Cooperates with ATG2B, also located in 14q32.2 and included in the 700 kb duplication NC_000014.9:g.95696766_96390792dup (on Assembly GRCh38).

Encoded in 3 exons spanning 7 Kb.

NM_001271904 encodes the longest transcript; 3 other transcripts encode the same protein with differences in the 5UTR.

Protein of 139 amino acids.

in CD34+ hematopoietic progenitors and during erythroïd and megakaryocyte differentiation.

Overexpression of GSKIP enhances hematopoietic progenitor differentiation, particularly of megacaryocytes and cooperates with classical driver mutations.

Founder defect in families originated from West-Indies.

Head-to-tail 700 kb tandem duplication (g.95696766_96390792dup).

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.

Encoded in 16 exons spanning 42 Kb.

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.

Protein of 1132 amino acids.

Blood cells.

Telomerase activity, essential for maintaining telomere length.

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).

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

http:\/\/www.ncbi.nlm.nih.gov\/clinvar\/variation\/208237\/ ClinVar : SCV000224007-4010