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Leukemia is characterized by

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Title: Leukemia is characterized by


1
Leukemia is characterized by hyperproliferation o
f immature white blood cells
Leukemic patient
normal person
red blood cells
white blood cell
hyperproliferation of white blood cells
2
Different types of leukemia affect different stem
cell types and distinct stages in their
development
Molecular Cell Biology Lodish et al. Fig. 24.1
3
Chronic myelogenous leukemia (CML) Annual
incidence 1/100,000 people (15 of all
leukemias) Median age 30-60 yrs Median
survival 4 yrs with conventional chemotherapy
6 yrs with aIFN therapy allogeneic bone marrow
transplantation may cure the patient
4
Chronic myelogenous leukemia (CML) Arises in a
particular bone marrow stem cell The
granulocyte precursor Gives rise to neutrophils
, basophils megakaryocytes. Neutrophils--
fight infection by phagocytosis Basophils--
release immune modulators, e.g., histamines,
Prostaglandins Platelets- cell fragments of
megakaryocytes.
5
CML arises in a stem cell that is a granulocyte
precursor
Molecular Cell Biology Lodish et al. Fig. 24.1
6
Nature 1973 243290-3 A new consistent
chromosomal abnormality in CML identified by
quinacrine fluorescence and Giemsa
staining. Rowley JD.
Janet Rowley in 1998 Upon receiving the Lasker
Award
7
A chromosomal translocation triggers CML
Leukemic patient
Normal individual
Chr. 22
9 22 Translocation The Philadelphia chromosome
Chr. 9
8
A characteristic karyotype indicates CML
Karyotype courtesy of L. J. Beauregard, Eastern
Maine Medical Center
9
Acute lymphoblastic leukemia (ALL) Affects
precursor of leukocytes (B and T cells) Ph
chromosomes in 20 of adult ALL 2-5 of childhood
ALL In adults prognosis very poor (Only 35- 40
of adults with ALL survive 2 years) Bone marrow
transplant the only long term treatment
10
Abelson was first identified as the oncogene
carried by Abelson leukemia virus, which causes
pre-B cell Lymphoma in mice
Abelson and Rabstein, Cancer Res 30, 2213 (1970)
11
The v-abl containing retrovirus was recovered
from a tumor found in mice infected by Moloney
Leukemia virus
12
The Philadelphia chromosome translocation fuses
the bcr and abl genes
normal individual
Leukemic patient
bcr
Bcr-abl
Chr. 22
abl
9 22 Translocation fuses Bcr and Abl
Chr. 9
De Klein et al. Nature 300, 765 (1982)
Groffen et al. Cell 36, 93 (1984)
13
The translocation results in production of a
fusion protein that joins the amino-terminal end
of the BCR protein to most of the Abl protein
The Cell, G. Cooper, Fig. 15.25
14
Fluorescence in situ hybridization (FISH) A tool
for diagnosing CML
Zymed.com
5 of abl in situ probe
3 of abl in situ probe
15
Abelson kinase
  • A fatty-acid modified and actin-binding
  • non-receptor tyrosine kinase

Actin-binding
Myristate
SH2
F
G
SH3
kinase
16
Oncogenic versions of Abelson
Abl
Actin-binding
SH2
F
G
SH3
kinase
v-abl
Gag
F
G
Bcr-Abl
Bcr
F
G
17
Src is normally inactive due to intramolecular
inhibition
18
The structure of Abl reveals a novel mode of
intramolecular inhibition
Nagar et al. Cell 112859 (2003)
19
Src and Abl Distinct yet analogous modes of
regulation
Harrison Cell 112, 737 (2003)
20
A multistep mechanism for activating Src
Harrison Cell 112, 737 (2003)
21
A proposed mechanism for activating Abl
Harrison Cell 112, 737 (2003)
22
Abls Kinase Domain In complex With
the inhibitor Gleevac
Kuriyan lab website
23
Clinical Course Phases of CML
Advanced phases
Chronic phase Median 56 years stabilization
Accelerated phase Median duration 69 months
Blast crisis Median survival 36 months
Provided by Gleevec.com
24
Blast crisis is thought to involve additional
genetic changes that are only beginning to be
characterized
Suggested events Mutations in
p53 MSI2/HOXA9 fusion protein AML1/EVI-1
fusion protein Ras mutations
25
Therapy for CML how do you evaluate whether
the drug is working?
Hematologic Response Cytogenetic Response
Complete Major Normal peripheral
blood count Complete 0 Ph No immature
cells Partial 1-35 Ph
Minor 3695 Ph
Modified from Gleevec.com
26
Therapeutic Options for CML
  • Allogeneic stem cell transplantation (SCT)
  • Interferon-alpha (IFN-?)based treatments
  • Chemotherapy with hydroxyurea, busulfan
  • Gleevec (imatinib mesylate, STI571)

From Gleevec.com
27
Until recently interferon-alpha treatment Was the
gold-standard in CML Even though its mechanism of
action IS STILL NOT UNDERSTOOD
Data of the Italian Cooperative Study group on
Chronic Myeloid Leukemia. Blood 199892 15411548
IFNinterferon-alpha, CHT conventional
chemotherapy
28
Abls Kinase Domain In complex With
the inhibitor Gleevac
Kuriyan lab website
29
Gleevec in chronic phase CML
Chronic Phase CML
1.0
Major cytogenetic response
0.9
0.8
Complete cytogenetic response
0.7
Fraction of patients that responded
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
1
2
3
4
5
6
7
8
9
10
Months Since Start of Treatment
Data Novartis Pharmaceuticals Corporation
30
Drug was discontinued for adverse events in 1
of patients in chronic phase, 2 in accelerated
phase, and 5 in blast crisis
31
Unfortunately, natural selection is a powerful
process
We now know of over 30 different mutations that
can cause BCR-ABL to become resistant to
imatinib, says Dr. Charles Sawyers of UCLAs
Jonsson Cancer Center. In patients with newly
diagnosed disease, we are seeing resistance to
imatinib in about 4 percent of patients per year.
The further the disease has progressed before
initiating imatinib treatment, the greater the
chances are that resistance will arise.
32
A possible solution a new generation of kinase
inhibitors that Still inhibit Gleevec-resistant
tumors
aka Dasatinib
Inject Luciferase-expressing tumor cells
Science 2004 305399-401
33
Dasatinib FDA approved for patients with relapses
NCI Cancer Bulletin October 5, 2006
aka Dasatinib
Inject Luciferase-expressing tumor cells
34
Dasatinib FDA approved for patients with relapses
NCI Cancer Bulletin October 5, 2006
Phase II trials suggest Dasatinib effective in
Blast-Crisis Patients with Gleevec-resistant
tumors
NCI Cancer Bulletin May 2 2007
Phase II trials suggest Dasatinib effective in
ALL patients with Gleevec-resistant tumors
NCI Cancer Bulletin May 29 2007
35
Gleevec also has promise in other tumors
e.g., Gastrointestinal Stromal Tumors 90 of
malignant GISTs harbor a mutation in c-kit
leading to KIT receptor autophosphorylation and
ligand-independent activation
http//www.answers.com/topic/gist-2-jpg-1
36
Gleevec also has promise in other tumors
e.g., Gastrointestinal Stromal Tumors 90 of
malignant GISTs harbor a mutation in c-kit
leading to KIT receptor autophosphorylation and
ligand-independent activation
Does not respond to chemotherapy (lt10
response) Only can be effectively treated if the
entire tumor Can be removed surgically Without
this median survival 1-2 yrs
37
With Gleevec treatment 50 of patients
respond Tumors shrink in size and disease
symptoms are greatly reduced
Report from the FDA Approval Summary Imatinib
Mesylate in the Treatment of Metastatic and/or
Unresectable Malignant Gastrointestinal Stromal
Tumors Dagher et al. Clinical Cancer
Research3034 30343038, October 2002
38
April 17, 2008
Gleevec treatment also reduces risk or
recurrence After surgical removal of GISTs
97 of patients treated with Gleevec had no
recurrence after 1 year Versus 83 of those
receiving placebo
39
GIST Long term outcome ?
Many patients who initially respond
develop secondary resistance to Gleevec and
relapse Cause second site mutations in c-kit!
40
GIST Long term outcome ?
Many patients who initially respond
develop secondary resistance to Gleevec and
relapse Cause second site mutations in c-kit!
Approach Develop new drugs targeted against
c-kit e.g., AMG706, SU11248
Current Oncology Reports (2005) 7 293-299
41
An alternate approach broader spectrum
inhibitors that hit multiple targets
Sunitinib targets Abl/PDGF Receptor, Src, and
VEGF Receptor
FDA approved after Phase III clinical trial
reveal efficacy in GIST patients whose Tumors
are resistant to Gleevec
George Demetri, MD
NCI Cancer Bulletin Oct. 31 2006
42
But what does Abl normally do?
43
Insights from the mouse model
abl mutant mice are viable but runted
and have a shortened lifespan They also have
problems with male fertility
B cell maturation osteoblasts and bone
formation Truncation of C-terminus leaving
an intact kinase has same phenotype as the
null mutant
44
Abelson has a twin brother
Abl
Actin-binding
SH3
SH2
kinase
F
G
89
94
27
34
F
G
Arg
45
Are Abl and Arg redundant?
arg mutant mice have behavioral defects
(Arg is expressed in the brain at high levels)
abl arg double mutants have defects in neural
tube
abl arg
Wild-type
46
BCR-Abl affects multiple cell functions
Proliferation differentiation
Stem cell turnover
BCR-Abl
Cytoskeleton/ adhesion defects
Apoptosis
Adapted from Jörgensen, 2001. Hem. Onc.
47
Abl may play roles in the nucleus in response to
DNA damage
ATM can phosphorylate Abl in response to DNA
damage Abl may stabilize p53
Van Etten, TICB 9 179-186
48
Abl may transmit signals in response to cell
matrix adhesion
Proteins that bind or are phosphorylated
by Bcr-Abl
Salesse and Verfaille Oncogene 21, 8605 (2002)
49
In the fruit fly Abl transmits signals from
axon guidance receptors to the cytoskeleton
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