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Leukemia
Abnormal proliferation of certain blood
cells at the expense of others
Malignant cells are often
undifferentiated, immature
progenitors
Lymphoid leukemias are caused by
defects in immune cells (such as B
and T cells)
Myeloid leukemias are caused by
changes in myeloid cells (such as
monocytes and megakaryocytes)
Disease-Associated Mutations
A mutation is a change in the normal base pair sequence of DNA
Disease-Associated Mutations
Alter Protein Function
Functional protein
Nonfunctional
or missing
protein
Trisomy 21
Meiosis I/II
GATA1
mutation
TMD
AMKL
Birth
2-3 years
Additional mutations
JAK2
JAK3
FLT3
MPL
RAD21
STAG2
CTCF
EZH2
Excessive
proliferation
Spontaneous regression
Sandeep Gurbuxani MD/PhD
AMKL
population
Survival
International ALL
Ponte di Legno
Working Group
1995-2004
Buitenkamp et al,
Blood 2014
8 yr EFS
64%
8 yr OS
74%
Childrens Oncology
Group
1999-2005
Maloney et al, Blood
2010
81% vs
89% vs
2 yr TRM
7%
2% vs
5 yr EFS
70%
5 yr OS
86%
78% vs
UK ALL study
3040 children without
2003-2011
DS
Patrick et al, BJH 2014 86 children with DS
5 yr EFS
66%
5 yr OS
70%
90% vs
88% vs
92% vs
Mouse Models of DS
mice
Ts1Cje
DSCR
DSCR
Ts16
Tc1
Ts65Dn Ts1Cje
Ts1Rhr
AML1
CBR1
CBR3
C21orf5
AK009785
KIAA0136
CHAF1B
CLDN14
SIM2
HLCS
DSCR6
DSCR5
TTC3
DSCR3
DYRK1A
As-DYRK1
KCNJ6
KCNJ15
As-KCNJ15
ERG
ETS2
DSCR2
WDR9
HMG14
WRB
C21orf13
SH3BGR
B3GALT5
IGSF5
PCP4
DSCAM
As-DSCAM
BACE2
MX1
C21orf1
ERG
DYRK1A
CHAF1B
HMGN1
Conclusions
Trisomy 21 predisposes children to
leukemia
Children with DS have a better prognosis
for AMKL, but a worse prognosis for B-ALL
Less toxic and more effective therapies are
needed for both forms of cancer
Research aimed at understanding the
nature of the predisposition and the genetic
basis of the disease will identify new
strategies to treat these tumors
Current studies
Mouse models of DS-AMKL and DSALL have been created
They have improved our understanding
of the genetic basis of the disease
They provide a platform to test new
therapies
JohnCrispino,PhD
jcrispino@northwestern.edu