IDH - siesonline

Le
nuove
mutazioni
oltre
JAK2:
IDH1/2
e
LNK
Dr.ssa
Lisa
Pieri

First
report
of
IDH1
muta5ons
in
myeloid
malignancies:
detected
by
sequencing
an
AML
genome
,
preferen5ally
clustering
with
intermediate
risk
AMLs
Muta5ons
first
discovered
in
gliomas
and
secondary
glioblastomas
AML
(16/188
mutated
cases,

8%)
R132C
8/16
(50%)
R132H
7/16
(44%)
R132S
1/188
IDH2
R172
0/188
Gliomas
and
secondary
glioblastomas
(about
80%
mutated)
R132C
7/161
(4%)
R132H
142/161
(88%)
R132S
4/161
R172
0/188
No
indipendent
prognos5c
value
with
respect
to
overall
survival
in
mul5variate
analysis
Mardis E et al, NEJM 2009; 361:1058-66
Yan H et al. NEJM 2009; 360:765-9

NADP+-dependent isocitrate dehydrogenase genes, IDH1 and IDH2
IDH1 (Chr 2q33.3)
IDH2
(Chr 15q26.19)
COINVOLTI
NEL
CICLO
DI
KREBS

IDH1 and IDH2 mutations lead to “biochemical gain of function”
• IDH, Isocitrate dehydrogenase (IDH1 =cytoplasmic; IDH2 = mitocondrial): NADPdependent
enzyme that catalyze the oxidative decarboxilation of isocitrate to α-
ketoglutarate, with concomitant production of NADPH.
Isocitrate
NADP
IDH1
IDH2
NADPH
α-ketoglutarate
NADPH
IDH1 R132
IDH2 R172
2-hydroxyglutarate
NADP
Mutated
proteins
harbour
a
new
enzyma5c
ac5vity:
produc5on
and
accumula5on
of
2HG,a
rare
metabolite
normally
present
at
very
low
levels
in
healthy
cells
Yan H et al. NEJM 2009; 360:765-9
Gross S et al, JEM, 2010; 207:339

Reduc5on
of
NADPH
and
glutathione
and
increase
of
ROS
Reduc5on
of
aKG,
that
normally
ac5vate
proline
hydroxylase
that
inac5vate
HIF1a,
and
consequently
increasing
in
HIF1a
and
its
associated
target
Homozygous
missense
muta5ons
have
not
been
iden5fied:
the
WT
protein
is
necessary
to
produce
NADPH
Abdel‐Wahab

and
Levine,
JEM
2010,207‐4,
677‐680

Different mutations have the same effect
IDH
muta5ons
R
132
(IDH1)
R
140
(IDH2)
R
172
(IDH2)
IDH
muta5ons’
frequency
in
78
AML
samples
7.7%
9%
4.4% 15.4%
Ward et al, Cancer Cell 17, 225–234, March 16, 2010

Somatic mutations of IDH1 and IDH2 in the leukemic
transformation of myeloproliferative neoplasms
31%
of
BP‐MPN
0%
of
CP‐MPN
Acquired
early
during
the
progression
to
leukemia
Green A, Beer P, NEJM 2010; 362:369-70

Gene;c
analysis
of
leukemic
transforma;on
in
MPNs
All four possible
mutational
combinations were
observed
IDH1
muta5ons
is
most
commonly
observed
in
pts
with
WT
JAK2,
TET2,
ASXL1
Abdel‐Wahab
O,
Cancer
Research
2010;,70(2)

Tefferi et al., Leukemia (2010) 24, 1302–1309

IDH
muta5ons
were
infrequent
in
chronic‐
or
fibro5c‐phase
disease
and
significantly
more
prevalent
in
blast‐phase
disease
IDH
co‐occurs
with
a
JAK2,
MPL
or
TET2
muta5on,
and
muta5onal
frequency
did
not
appear
to
be
influenced
by
either
the
type
of
the
coexis5ng
muta5on
or
the
presence
or
absence
of
each
specific
muta5on
IDH‐mutated
cases
were
more
likely
to
be
nullizygous
for
JAK2
46/1
haplotype
Tefferi et al., Leukemia (2010) 24, 1302–1309

Clinical
correlates
and
prognos0c
relevance
in
PMF
IDH‐mutated
chronic‐phase
PMF
cases
ohen
belonged
to
a
low‐
or
intermediate‐risk
category
(p=0.32)
IDH‐mutated
blast‐phase
PMF
was
less
likely
to
display
complex
karyotype
(p
0.001)
CP‐PMF
BP‐PMF
BP‐MPN

Novel
muta+ons
in
the
inhibitory
adaptor
protein
LNK
(SH2B3)
drive
JAK‐
STAT
signaling
in
pa+ents
with
myeloprolifera+ve
neoplasms
LNK
exon
2
muta0ons
(Pleckstrin‐homology
domain):
603_607delGCGCT
and
613C→G:
dele5on
of
five
base
pairs
and
a
missense
muta5on
leading
to
a
premature
stop
codon
Found
in
1
pt
JAK2WT
PMF
622G→C:
missense
muta5on
yielding
a
subs5tu5on
of
glutamine
for
glutamic
acid
(E208Q)
Found
in
1
pt
JAK2WT
ET
Oh
ST
et
al,
Blood.
2010
Aug
12;116(6):988‐92
6%
of
33
JAK2
WT
MPN

Oh
ST
et
al,
Blood.
2010
Aug
12;116(6):988‐92

Oh
ST
et
al,
Blood.
2010
Aug
12;116(6):988‐92

ID DG JAK2V617F IDH LNK
1
2
PMF
AML
PMF
AML
VF
29%
VF
30%
WT
WT
WT
WT
WT
WT
658>A;
G220R
WT
WT
644C>T;A215V
139
pts:
•
61
postMPN‐AML
•78
CP‐MPN
3
4
PMF
AML
PMF
AML
NA
NA
VF
22%
VF
NA
NA
IDH2
R140Q
IDH2
R140Q
WT
644C>T;A215V
685‐691_delGGCCCCG,
955_delA
685‐691_delGGCCCCG
,955_delA
8
mutated
cases
(13%)
9.8%
mutated
in
BP‐MPN
5
PMF
AML
WT
WT
WT
WT
WT
688C>T;A223V
700G>A;
D234N
88%
had
PMF
in
CP
6
PMF
AML
WT
WT
WT
WT
659G>T;
G220V
WT
7 postPMF‐AML VF
25% WT 685G>A;
G229S
8 postPV‐AML VF
80% WT 624G>A;
E208E
6
missense
muta5ons
1
synonymous
muta5on
2
dele5ons
(same
case)
Muta5onal
“hot
spot”
No
clear
genotype‐phenotype
correla5on
All
in
PH
domain
or
just
distal
to
PH
domain
Pardanani
et
al.
Leukemia.
2010
Oct;24(10):1713‐8.

LNK Mutations in JAK2 Mutation–Negative Erythrocytosis
8
pts
with:
Erythrocytosis
low
erythropoie5n
levels
absence
of
JAK2,
MPL,
EPOR
muta5ons
2
mutated
pts:
622G→T:
nonsense
muta5on
resul5ng
in
the
subs5tu5on
of

a
stop
codon
for
glutamic
acid
(E208X),
with
trunca5on
of
PH
and
SH2
domain.
644C→T:
missense
muta5on
resul5ng
in
the
subs5tu5on
of
valine
for
alanine
A215V),
absent
in
lymphocytes.
Conserva5ve
aminoacid
change.
Also
found
in
JAK2V617F
nega5ve
BP‐PMF.
LNK
muta;ons
are
part
of
the
“missing
link”
in
the
pathogenesis
of
JAK2
muta;on–nega;ve
“idiopathic”
erythrocytosis
or
polycythemia
vera.
Lasho
TL
et
al,
N
Engl
J
Med.
2010
Sep
16;363(12):1189‐90

Dr.ssa
ElisabGa
Antonioli
Dr.
Niccolò
Bartalucci
Dr.ssa
Flavia
Biamonte
Dr.ssa
Costanza
Bogani
Dr.ssa
Paola
Guglielmelli
Dr.ssa
Tiziana
Fanelli
Dr.ssa
Elisa
Malevol0
Dr.ssa
Serena
Mar0nelli
Dr.
Alessandro
Pancrazzi
Dr.ssa
Chiara
Paoli
Dr.ssa
Ambra
Spolverini
Dr.
Lorenzo
Tozzi
Thanks
to:
Prof.
Alessandro
Vannucchi