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Familial platelet disorder with predisposition to
acute myelogenous leukemia (FPD/AML)
Paula G Heller
Hematologia Investigacion, Instituto de Investigaciones Medicas Alfredo Lanari, Universidad de Buenos
Aires, Unidad Ejecutora IDIM-CONICET, Combatientes de Malvinas 3150 Buenos Aires 1427, Argentina.
(PGH)
Published in Atlas Database: July 2008
Online updated version : http://AtlasGeneticsOncology.org/Kprones/FamPlateletDisAMLID10079.html
DOI: 10.4267/2042/44528
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2009 Atlas of Genetics and Cytogenetics in Oncology and Haematology
been found in these patients, providing a potential
explanation for low platelet counts. Bleeding tends to
be more severe than expected according to the degree
of thrombocytopenia due to the presence of associated
platelet dysfunction and results in a significant bleeding
diathesis, which, although not severe, might be lifethreatening after surgery or child-bearing. Platelet
aggregation is abnormal in response to several platelet
agonists although the mechanisms underlying this
defect are not clear. Both platelet storage pool
deficiency and impaired alphaIIbbeta3 integrin
(GPIIbIIIa) activation and fibrinogen binding have
been described. The presence of platelet dysfunction
seems to be a constant feature of this disorder and,
although frequently associated to thrombocytopenia,
some affected individuals display platelet counts at the
lower limit of normal.
Identity
Alias
Familial platelet disorder with predisposition to
myeloid malignancy
Inheritance
Familial platelet disorder with predisposition to acute
myelogenous leukemia is a rare autosomal dominant
disorder caused by heterozygous germline mutations in
transcription factor RUNX1. Only fifteen pedigrees
have been reported to date. The disease appears to have
complete penetrance and affected individuals are born
at the expected frequency for an autosomal dominant
trait. There have been no reports of parental
consanguinity among the pedigrees described so far,
and males and females are equally affected. Together
with CEBPA-associated leukemia and familial
monosomy 7, FPD/AML represents one of the few
identified genetic disorders underlying pure familial
leukemia cases.
Neoplastic risk
Patients with FPD/AML are predisposed to myeloid
malignancies, including AML and MDS. Several AML
FAB subtypes have been reported to occur, including
M1, M2, M4 and M5, while refractory anemia with
excess blasts, chronic myelomonocytic leukemia and
hypoplastic MDS with myelofibrosis have been
described among the cases with MDS.
The rate of myeloid malignancies ranges between 20 to
65% and peaks at the fourth decade of life. Median age
of leukemia onset is 37 years old, ranging from 6 to 75.
Germline RUNX1 mutations seem to be insufficient by
themselves for leukemia development and acquisition
of additional cooperating events are required. Several
cytogenetic abnormalities have been identified in
FPD/AML patients who develop myeloid neoplasms,
including del(5q), -7/del(7q), +8, del(11q), 11q23
Clinics
Phenotype and clinics
Familial platelet disorder with predisposition to acute
myelogenous leukemia is characterized by inherited
thrombocytopenia, platelet function defect and a
lifelong risk of myelodysplastic syndrome (MDS) and
acute
myelogenous
leukaemia
(AML).
Thrombocytopenia is usually mild to moderate and is
characterized by normal platelet size. Decreased
expression of the thrombopoietin Mpl receptor has
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(7)
527
Familial platelet disorder with predisposition to acute myelogenous leukemia (FPD/AML)
the transactivation domain is enclosed in exons 7b and
8. Transcription yields several isoforms, which are
generated by alternative splicing, different promoter
usage and differential usage of polyadenylation sites.
Most abundant species include isoforms RUNX1b and
RUNX1c, which encode the full-length protein.
Transcription of RUNX1c is initiated at the distal
promoter and includes exons 1 and 2, while RUNX1b
is regulated by the proximal promoter and starts at exon
3, both including exons 4, 5, 6, 7b and 8, according to
nomenclature described by Miyoshi and colleagues.
Thus, RUNX1b and c differ at their amino (N)-terminal
end, being the former 27 amino acids shorter than the
latter, although there appears to be no relevant
functional differences between them. In contrast, the
shorter RUNX1a isoform is a truncated variant
spanning exons 3 to 7a with DNA-binding but no
transactivation activity which may potentially interfere
with RUNX1b and c function, acting as a negative
regulator.
Protein
Description: The RUNX1b protein consists of 453
amino acids with 48 kDa molecular weight, RUNX1c
comprises 480 amino acids while RUNX1a is formed
by 250 amino acids. RUNX1 belongs to a family of
heterodimeric transcription factors which include
RUNX2 and RUNX3, all of them forming heterodimers
with CBFbeta.
RUNX factors comprise an N-terminal region named
the runt homology domain (RHD), because of its
homology to Drosophila Runt protein, which mediates
both DNA binding and heterodimerization with
CBFbeta, and a carboxyl(C)-terminal region
responsible
for
transcriptional
regulation.
Heterodimerization with CBFbeta enhances its DNAbinding capacity and protects it from proteolytic
degradation. RUNX1 binds to the DNA consensus
sequence TGTGGT and functions as a transcriptional
activator or repressor, depending on promoter structure,
the spliced variant expressed and the cellular context.
RUNX1 is believed to act as a transcriptional
organizer, recruiting other lineage-specific transcription
factors to their promoters.
Expression: During embryogenesis, RUNX1 can be
detected in hematopoietic stem cells and endothelial
cells of the AGM region, while after organogenesis,
RUNX1 is predominantly expressed in the
hematopoietic system. Highest levels are found in
thymus, bone marrow and peripheral blood.
Localisation: Nucleus.
Function: The RUNX1/CBFbeta transcription complex
is critical for normal hematopoiesis, as revealed in
RUNX1-null mice, which die during embryonic
development due to failure to establish definitive
hematopoiesis.
rearrangements, del (20q) and +21. On the other hand,
no mutations have been found in the remaining
RUNX1 allele in FPD/AML patients who developed
leukemia.
The mechanisms by which germline RUNX1 mutations
predispose to leukemia remain unclear. RUNX1
deficiency in adult mice (RUNX1 +/- and -/-) is
accompanied by an increase in committed myeloid
progenitors, which could be explained by alteration in
proliferative and/or self-renewal capacity or,
alternatively, by partial block in differentiation. These
abnormalities result in an expanded pool of progenitors
susceptible to second mutations. Besides, there is
evidence that RUNX1 functions as a tumor suppressor
gene through up-regulation of p14ARF, which
enhances p53 tumor-suppressive activity by binding to
its negative regulator Mdm3. RUNX1 is believed to be
haploinsufficient for tumor suppression, providing an
additional explanation for leukemia presdisposition
seen in this disorder.
Treatment
Recommendations for management of FPD/AML
patients are lacking due to the low frequency of this
disorder and need to be assessed individually. Bleeding
should be managed as for other platelet function
disorders, according to severity of bleeding
manifestations. Patients with FPD/AML who develop
AML or MDS are candidates for hematopoietic stem
cell transplantation. As thrombocytopenia in FPD/AML
is frequently mild or moderate and may be overlooked,
mutational screening of potential sibling donors is
required to avoid transplantation of stem cells
harbouring the same RUNX1 mutation.
Prognosis
Platelet counts tend to remain stable throughout
lifetime except when development of myeloid
malignancy occurs. Prognosis depends on disease
transformation to MDS/AML, the risk of which seems
to vary according to the type of RUNX1 mutation and
its effect on RUNX1 function.
Genes involved and proteins
RUNX1 (runt-related transcription factor
1)
Alias
AML1 (acute myeloid leukemia 1)
CBFA2 (core-binding factor, alpha subunit 2)
Location
21q22.12
DNA/RNA
Description: The RUNX1 gene encompasses 12 exons.
Exons 3 to 5 encode the DNA-binding domain, while
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(7)
Heller PG
528
Familial platelet disorder with predisposition to acute myelogenous leukemia (FPD/AML)
Heller PG
Diagram of the RUNX1 gene and the three major mRNA and protein species, according to the nomenclature described by Miyoshi et al.
Exons are represented by boxes, solid boxes indicate coding regions, while open boxes represent untranslated regions. RUNX1a differs
from RUNX1b and RUNX1c at the C-terminal half of the protein, while RUNX1c differs at the N-terminal end. The DNA-binding runt
homology domain (RHD) and the transactivation domain (TAD) of the protein are depicted.
although mutations in the C-terminal region have been
found in three cases. Most frequently involved amino
acids are those included in the three loops which
contact the DNA-interface, comprising amino acids 7487, 139-145 and 171-177.
In vitro functional studies have shown that RHD
mutations
abrogate
the
DNA-binding
and
transactivation capacity while, according to whether
they retain or loose their ability to heterodimerize with
CBFbeta, they interfere with the wild-type protein in a
dominant-negative
manner
or
act
through
haploinsufficiency, respectively.
On the other hand, C-terminal mutants have an
enhanced capacity to bind DNA, due to lack of a DNAbinding inhibitory domain, and interact strongly with
CBFbeta and are therefore expected to strongly repress
the normal allele. Dominant-negative mutations seem
to cause higher predisposition to leukemia than those
acting via haploinsufficiency.
Recently, constitutional microdeletions on 21q
encompassing the RUNX1 locus have been reported to
cause congenital thrombocytopenia associated with
mental retardation, developmental delay and
predisposition to leukemia.
Somatic: RUNX1 is one of the genes most frequently
dysregulated in leukemia, mostly through chromosomal
translocations, mutations and amplifications. RUNX1
was originally cloned as the target of the t(8;21)
chromosomal translocation characteristic of AML
which encodes the RUNX1 (AML1) - ETO fusion
product, and was subsequently found to be involved in
other chromosomal translocations in both myeloid and
lymphoblastic neoplasms, such as t(12;21) and t(3;21),
which generate TEL - RUNX1 and RUNX1 MDS1/EVI1 transcripts. Besides, acquired point
mutations in the RUNX1 gene have been reported in
5% sporadic leukemia, predominantly in FAB subtype
M0, where they are frequently biallelic. Moreover,
mutations have been detected in
Although it is dispensable for the maintenance of adult
hematopoietic stem cells, it plays an essential role in
the development of the megakaryocytic and lymphoid
lineages.
The role of RUNX1 in megakaryocytes is beginning to
be revealed. In vitro studies suggest that RUNX1
participates in megakaryocyte lineage commitment and
divergence from the erythroid pathway. While
FPD/AML patients show a decrease in megakaryocyte
colony growth, heterozygous or conditional biallelic
deletion of RUNX1 in mice leads to increased
megakaryocyte growth with a partial arrest in
differentiation. Besides, several abnormalities in the
lymphoid lineage have been revealed in mouse models,
including defects in B- and T-cells. In contrast, despite
its expression in monocytes and neutrophils and its
regulation of genes specific to these cells, lack of
RUNX1 has no apparent effects in monocyte or
neutrophil number or function. Known targets of
RUNX1 in hematopoietic cells include cytokines, cell
receptors and differentiation molecules, such as GMCSF, IL-3, myeloperoxidase, neutrophil elastase, MCSF and TCR receptors.
Homology: Other members of the RUNX family
include RUNX2 and RUNX3, which are alternative
heterodimeric parterns for CBFbeta.
Mutations
Note: Germline RUNX1 mutations Linkage to
chromosome 21q22.12 was established in 1996 in a
large FPD/AML pedigree described by Dowton and
colleagues. Among genes mapping to this region,
RUNX1 emerged as an attractive candidate for this
disorder and subsequently, RUNX1 mutations were
identified in several FPD/AML patients. Fourteen
different mutations have been detected in fifteen
pedigrees reported so far, including missense, nonsense
and frameshift mutations and a large intragenic
deletion. Most mutations are clustered in the RHD,
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(7)
529
Familial platelet disorder with predisposition to acute myelogenous leukemia (FPD/AML)
Heller PG
Schematic structure of RUNX1b protein and position of germline mutations identified in fifteen FPD/AML pedigrees. Missense mutations
are show at the upper side of the panel in pale blue, while nonsense and frameshift mutations are represented in green at the bottom. A
large intragenic deletion was found in one case. * indicates this mutation has been identifed in two pedigrees.
Levanon D, Glusman G, Bangsow T, Ben-Asher E, et al.
Architecture and anatomy of the genomic locus encoding the
human leukemia-associated transcription factor RUNX1/AML1.
Gene. 2001 Jan 10;262(1-2):23-33
approximately 8% MDS patients and in 45% secondary
MDS and AML. While AML mutations occur mainly
in the RHD, both N-terminal and C-terminal mutations
have been reported in MDS. On the other hand,
RUNX1 amplification occurs predominantly in
pediatric LLA.
Michaud J, Wu F, Osato M, Cottles GM, Yanagida M, et al. In
vitro analyses of known and novel RUNX1/AML1 mutations in
dominant familial platelet disorder with predisposition to acute
myelogenous leukemia: implications for mechanisms of
pathogenesis. Blood. 2002 Feb 15;99(4):1364-72
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acute myelogenous leukemia (FPD/AML). Atlas Genet
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