1. hyperproliferation of white blood cells
Leukemia is characterized by
hyperproliferation and bone marrow exit
of immature white blood cells
normal person
Leukemic patient
red blood cells
white blood cell
hyperproliferation of white blood cells

2. To understand leukemia we need to examine
development of the Hematopoietic System
self renewal
myeloid
lymphoid
self renewal
self renewal
granulocytes
Wikipedia 2

3. Different types of leukemia affect different stem cell types
and distinct stages in
their development
Molecular Cell Biology
Lodish et al. Fig. 24.1

4. Chronic myelogenous leukemia (CML)
Annual incidence: 1/100,000 people
(~15% of all leukemias)
Median age: yrs

5. Chronic myelogenous leukemia (CML)
Median survival before onset of new therapies:
4 yrs with conventional chemotherapy
6 yrs with aIFN therapy;
allogeneic bone marrow transplantation
may cure the patient

6. CML arises in a stem cell that is a granulocyte precursor
Molecular Cell Biology
Lodish et al. Fig. 24.1

7. The granulocyte precursor Gives rise to
Neutrophils-- fight infection by phagocytosis
Basophils-- release immune modulators, e.g., histamines, Prostaglandins
Platelets- cell fragments of megakaryocytes.

8. 1960: Nowell and Hungerford find that one copy of chromosome 22 is extremely short in CML patients
“The findings suggest a causal relationship between the chromosome abnormality observed and chronic granulocytic leukemia.”
Peter Nowell 8

9. Upon receiving the Lasker Award
Nature :290-3
“A new consistent
chromosomal
abnormality in
CML identified by
quinacrine fluorescence
and Giemsa staining.”
Janet Rowley in 1998
Upon receiving the Lasker Award

10. What is a chromosomal translocation?

11. A chromosomal translocation
triggers CML
Leukemic patient
Normal individual
Chr. 22
Chr. 9
9; 22 Translocation
The Philadelphia
chromosome

12. Here’s the characteristic karyotype of CML
L. J. Beauregard,
Eastern Maine Medical Center

13. Acute lymphoblastic leukemia (ALL)
In contrast,
Acute lymphoblastic leukemia (ALL)
affects precursors of leukocytes =B +T cells)

14. Acute lymphoblastic leukemia (ALL)
Ph+ chromosomes in 20% of adult ALL
2-5% of childhood ALL

15. Acute lymphoblastic leukemia (ALL)
In adults prognosis is poor
(80-90%of will have remissions but half will experience a relapse,
making overall cure rate ˜40%)
Bone marrow transplant
the only long term treatment

16. Chromosomal rearrangements are a hallmark of leukemia,
being present in 70-90% of cases
Table 4.5 The Biology of Cancer (© Garland Science 2007) 16

17. Why is this the case?
Table 4.5 The Biology of Cancer (© Garland Science 2007) 17

18. our adaptive immune system Via production of antibodies
B cells and T cells
Are the workhorses of
our adaptive immune system
Via production of antibodies
or T cell receptors
Molecular Biology of the Cell Alberts et al

19. Pathogens make millions of antigens and we cannot dedicate all 25,000
genes in the genome
just to make antibodies.
Molecular Biology of the Cell Alberts et al

20. Put antibodies together by a mix-and match approach!
What’s the solution?
Put antibodies together
by a mix-and match approach!
Molecular Biology of the Cell Alberts et al

21. This requires rearranging the DNA
Molecular Biology of the Cell Alberts et al

22. Cut the DNA here and religate
Molecular Biology of the Cell Alberts et al

23. Molecular Biology of the Cell Alberts et al
The result:
an antibody
light chain
Molecular Biology of the Cell Alberts et al

24. Since there are multiple types of each gene segment, there are thousands of possible V-D-J combinations Each B cell gets a unique combination
This slide gives current best numbers for human antibody segments. You could do some simple calculations like those in the notes of slide 25, “A unique recombination occurs in each B cell” to determine how many combinations are possible based only on the number of different segments.
K and λ refer to two distinct forms of light chains that exist in most vertebrates. An IgG molecule may have two K chains or two λ chains, but not both.

25. Since there are multiple types of each gene segment, there are thousands of possible V-D-J combinations Each B cell gets a unique combination
Isn't that amazing!
This slide gives current best numbers for human antibody segments. You could do some simple calculations like those in the notes of slide 25, “A unique recombination occurs in each B cell” to determine how many combinations are possible based only on the number of different segments.
K and λ refer to two distinct forms of light chains that exist in most vertebrates. An IgG molecule may have two K chains or two λ chains, but not both.

26. However sometimes this goes wrong,
and other genes are juxtaposed to the Ig or TCR genes

27. Rearrangement mistakes can also juxtapose
other genes with oncogenic consequences

28. The Philadelphia chromosome
translocation fuses
the bcr and abl genes
normal individual
Leukemic patient
bcr
Bcr-abl
Chr. 22
abl
Chr. 9
9; 22 Translocation
fuses Bcr and Abl
De Klein et al. Nature 300, 765 (1982)
Groffen et al. Cell 36, 93 (1984)

29. Abelson was first identified as the fusion protein oncogene
carried by Abelson leukemia virus,
which causes pre-B cell Lymphoma in mice
Abelson and Rabstein, Cancer Res 30, 2213 (1970)

30. The v-abl containing
retrovirus was recovered
from a tumor found
in mice infected by
Moloney Leukemia virus

31. In CML 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

32. In fact, different breakpoints in bcr
lead to slightly different Bcr-Abl fusion proteins
that are found in different cancers 32

33. the extreme N-terminal end of Abl
ALL delete
the extreme N-terminal end of Abl 33

34. Fluorescence In Situ Hybridization (FISH)
provides a tool for diagnosing CML
abl
bcr 34

35. Fluorescence In Situ Hybridization (FISH) a tool for diagnosing CML
fusion 22
bcr/abl
fusion 9
abl/bcr
abl
bcr
The current methd: PCR
BCR
ABL 35

36. Abelson encodes a fatty-acid modified and actin-binding
non-receptor tyrosine kinase
Actin-binding
Myristate
SH2 F G
SH3
kinase

37. Abelson kinase The front end looks a lot like Src!! Actin-binding
Myristate
SH2 F G
SH3
kinase

38. Oncogenic versions of Abelson
Abl
Actin-binding
SH2 F G
SH3
kinase
v-abl
Gag F G
Bcr-Abl
Bcr F G

39. What’s changed?? Abl v-abl Bcr-Abl Actin-binding SH2 SH3 kinase GagF G
SH3
kinase
v-abl
Gag F G
Bcr-Abl
Bcr F G

40. Remember this?
Src is normally
inactive due to
intramolecular
inhibition

41. The structure of Abl revealed
a novel mode of intramolecular inhibition
Nagar et al.
Cell 112:859 (2003)

42. Distinct yet analogous modes of regulation
Src and Abl
Distinct yet analogous modes of regulation
Harrison Cell 112, 737 (2003)

43. A multistep mechanism for activating Src
Harrison Cell 112, 737 (2003)

44. A proposed mechanism for activating Abl
Harrison Cell 112, 737 (2003)

45. But what does Abl normally do?

46. Insights from the mouse model
• abl mutant mice are viable but runted
a shortened lifespan
male infertility
B cell maturation issues
osteoblasts and bone formation defects

47. Insights from the mouse model
• Truncation of C-terminus leaving an intact kinase
has same phenotype as the null mutant

48. Why so mild?? 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

49. Abelson has a twin brother
Abl
Actin-binding
SH3
SH2
kinase F G
34%
89%
94%
27% F G
Arg

50. Are Abl and Arg redundant?
• arg mutant mice have behavioral defects
(Arg is expressed in the brain at high levels)

51. 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
Wild-type
abl; arg

52. Now let’s turn to Abl’s cell biological role52

53. Remember
Focal adhesions?
Alberts et al.
Fig

54. Focal adhesion proteins are phosphorylated by Abl helping mediate integrin signaling)54

55. Abl also phosphorylates regulators of the actin cytoskeleton55

56. Of course it’s even more complicated
Than that!
Bradley and Koleske jcs.biologists.org/cgi/content/ full/122/19/3441/FIG3 56

57. bundle actin filaments
Abl can also
directly regulate
cytoskeletal events
using its
C-terminal region to
bundle actin filaments
and
link them
to microtubules 57

58. hyperproliferation of white blood cells
But does this all help us
understand and treat leukemia?
normal person
Leukemic patient
red blood cells
white blood cell
hyperproliferation of white blood cells

59. BCR-Abl affects multiple cell functions
Proliferation & differentiation
Stem cell turnover S G 2 M 1 G0
BCR-Abl
Cytoskeleton/
adhesion defects
Apoptosis
Adapted from Jörgensen, Hem. Onc.

60. 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

61. To understand leukemia, we must start by learning more about the clinical progression of CML
Advanced phases
Chronic phase
Median 5–6 years stabilization
Accelerated phase
Median duration 6–9 months
Blast crisis
Median survival 3–6 months
Clinical Course: Phases of CML
CML progresses through 3 phases characterized by increasing refractoriness to therapy and
worsening clinical features and laboratory findings. These stages include chronic phase,
accelerated phase, and blast crisis. Although the majority of patients present in chronic phase
and then progress to accelerated phase, 25% to 40% of patients progress directly from chronic
phase to the terminal blast crisis phase without evidence of a transitional accelerated phase.1,2
Chronic phase. In the chronic phase, there are less than 10% blasts in peripheral blood and bone marrow, and the white blood cell (WBC) count at presentation is typically elevated to 20 x 109/L. Signs and symptoms may be mild initially and develop as the disease progresses. The chronic phase of CML may last 5 to 6 years before the disease accelerates.1,3
Accelerated phase. There are more than 10% to 15% (but less than 30%) blasts in either peripheral blood or bone marrow. Symptoms may increase and include unexplained fever, bone pain, splenomegaly, and hepatomegaly. Basophilia, decreased platelet counts, and cytogenetic progression may also be observed. The accelerated phase may last 6 to 9 months.1,3
Blast crisis. There are more than 30% blasts in peripheral blood or bone marrow and symptomatology is increased, especially relating to anemia and infection, central nervous system (CNS) disease, lymphadenopathy, and bleeding. Approximately 50% of patients have myeloid blast crisis, 25% have lymphoid blast crisis, and 25% are mixed.3 Patients with CML in blast crisis have a poor prognosis owing to the lack of effective therapy. This phase is rapidly fatal, with a median survival of 3 to 6 months.2,3
References
1. Hill JM, Meehan KR. Chronic myelogenous leukemia. Curable with early diagnosis and treatment. Postgrad Med ;106: ,
2. Faderl S, Kantarjian HM, Talpaz M. Chronic myelogenous leukemia: update on biology and treatment. Oncology ;13:
3. Cortes JE, Talpaz M, Kantarjian H. Chronic myelogenous leukemia: a review. Am J Med. 1996;100:
Provided by: Gleevec.com

62. Blast crisis is thought to involve additional
genetic changes that are only beginning
to be characterized

63. 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
•Deletion of the Ikaros transcription factor

64. Therapy for CML: how do you evaluate whether a drug is working?
Goals of Therapy for CML: Response Criteria
Response criteria in CML have been defined in terms of hematologic and cytogenetic responses.1,2
The first goal of therapy in patients with CML is to reduce the WBC count to near-normal levels.
Hematologic responses are defined by whether (1) peripheral cell counts have normalized and (2) immature myeloid cells are no longer present. Hematologic improvement must be maintained for 1 month to qualify as response. Disappearance of signs (eg, splenomegaly or hepatomegaly) and symptoms of disease is also required.
The second goal is to achieve a cytogenetic remission by reducing or eliminating cells that carry the Ph chromosome.
Cytogenetic responses are based on bone marrow analyses of dividing myeloid cells in metaphase to quantify the number of detectable Ph+ cells. Molecular techniques such as fluorescence in situ hybridization (FISH) and quantitative reverse transcription polymerase chain reaction (RT-PCR) are also used for detection of bcr-abl transcripts.2
Achieving a cytogenetic response has been associated with improved survival in interferon-alpha (IFN-) patients.3
A therapy that is well tolerated and has no or few side effects is also an important parameter.
References
1. Faderl S, Talpaz M, Estrov Z, et al. Chronic myelogenous leukemia: biology and therapy. Ann Intern Med ;131:
2. Sawyers CL. Chronic myeloid leukemia. N Engl J Med ;340:
3. Kantarjian HM, Smith TL, O’Brien S, et al. Prolonged survival in chronic myelogenous leukemia after cytogenetic response to interferon- therapy. Ann Intern Med ;122:

65. Therapy for CML: how do you evaluate whether a drug is working?
Hematologic Response Cytogenetic Response
– Complete: – Major:
Normal peripheral blood count Complete: 0% Ph+
No immature cells Partial 1-35% Ph+
– Minor:
36%–95% Ph+
Goals of Therapy for CML: Response Criteria
Response criteria in CML have been defined in terms of hematologic and cytogenetic responses.1,2
The first goal of therapy in patients with CML is to reduce the WBC count to near-normal levels.
Hematologic responses are defined by whether (1) peripheral cell counts have normalized and (2) immature myeloid cells are no longer present. Hematologic improvement must be maintained for 1 month to qualify as response. Disappearance of signs (eg, splenomegaly or hepatomegaly) and symptoms of disease is also required.
The second goal is to achieve a cytogenetic remission by reducing or eliminating cells that carry the Ph chromosome.
Cytogenetic responses are based on bone marrow analyses of dividing myeloid cells in metaphase to quantify the number of detectable Ph+ cells. Molecular techniques such as fluorescence in situ hybridization (FISH) and quantitative reverse transcription polymerase chain reaction (RT-PCR) are also used for detection of bcr-abl transcripts.2
Achieving a cytogenetic response has been associated with improved survival in interferon-alpha (IFN-) patients.3
A therapy that is well tolerated and has no or few side effects is also an important parameter.
References
1. Faderl S, Talpaz M, Estrov Z, et al. Chronic myelogenous leukemia: biology and therapy. Ann Intern Med ;131:
2. Sawyers CL. Chronic myeloid leukemia. N Engl J Med ;340:
3. Kantarjian HM, Smith TL, O’Brien S, et al. Prolonged survival in chronic myelogenous leukemia after cytogenetic response to interferon- therapy. Ann Intern Med ;122:
Modified from Gleevec.com

66. Therapeutic Options for CML
Allogeneic stem cell transplantation (SCT)
Interferon-alpha (IFN-)–based treatments
Chemotherapy with hydroxyurea, busulfan
Gleevec™ (imatinib mesylate, = STI571)
Therapeutic Options for CML
The current treatment options for patients with CML include allogeneic stem cell transplantation (SCT), IFN-–based regimens, chemotherapy with hydroxyurea or busulfan, and Gleevec™ (imatinib mesylate, formerly STI571).
Allogeneic SCT is currently the only therapy with the potential to “cure” CML. Access to the procedure is limited by availability of a suitable donor and by patient age (many centers do not accept candidates >55 years of age). Transplantation within 1 year of diagnosis is preferred.1 Approximately 15% to 20% of patients with CML meet these criteria for SCT.2 Five-year survival for patients transplanted during the chronic phase of the disease ranges from 54% to 70%; survival rates decrease and morbidity and mortality increase dramatically with advanced stages of disease.
IFN- induces hematologic responses in most patients and cytogenetic responses in some patients. The effects are dose-related; higher doses of IFN- correlate with higher rates of hematologic and cytogenetic response as well as more severe adverse events.3,4 Approximately 25% of patients discontinued therapy because of major side effects.5
Chemotherapy is of limited value in inducing cytogenetic responses, but it is effective in lowering WBC counts. These agents are generally considered to be palliative.6
Gleevec is a tyrosine kinase inhibitor that has shown very promising results in phase I and phase II clinical trials.
References
1. Faderl S, Talpaz M, Estrov Z, et al. Chronic myelogenous leukemia: biology and therapy. Ann Intern Med ;131:
2. Sawyers CL. Chronic myeloid leukemia. N Engl J Med ;340:
3. Faderl S, Kantarjian HM, Talpaz M. Chronic myelogenous leukemia: update on biology and treatment. Oncology ;13:
4. Silver RT, Woolf SH, Hehlmann R, et al. An evidence-based analysis of the effect of busulfan, hydroxyurea, interferon, and allogeneic bone marrow transplantation in treating the chronic phase of chronic myeloid leukemia: developed for the American Society of Hematology. Blood ;94:
5. Guilhot F, Chastang C, Michallet M, et al. Interferon alfa-2b combined with cytarabine versus interferon alone in chronic myelogenous leukemia. N Engl J Med ;337:
6. Hill JM, Meehan KR. Chronic myelogenous leukemia. Curable with early diagnosis and treatment. Postgrad Med ;106: ,
From Gleevec.com

67. 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 1998: –1548
IFN=interferon-alpha, CHT= conventional chemotherapy

68. This was an improvement But most patients still progressed
We needed a targeted therapy
Data of the Italian Cooperative Study group on
Chronic Myeloid Leukemia. Blood 1998: –1548
IFN=interferon-alpha, CHT= conventional chemotherapy

69. Gleevec blocks the ATP binding site
of the kinase domain
STI571 69

70. Abl’s Kinase Domain In complex With the inhibitor Gleevac
Kuriyan lab website

71. Months Since Start of Treatment
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
Gleevec™: Rapid Hematologic and Cytogenetic Response1
More than 50% of patients with MCR achieved their response within 3 months (median = 2.9 months) in chronic phase CML. In accelerated phase and blast crisis phase CML, similar results were obtained.
The median time to a hematologic response was 1 month, with a range of 0.9 to 9.3 months in the accelerated phase CML. The median time to a hematologic response was also 1 month for the other phases of CML.
Reference
1. Data on file. Novartis Pharmaceuticals Corporation, East Hanover, NJ.
0.3
0.2
0.1
0.0 1 2 3 4 5 6 7 8 9 10
Months Since Start of Treatment
Data: Novartis Pharmaceuticals Corporation

72. Months Since Start of Treatment
This is an awesome drug! Most patients survive 10+ years
Chronic Phase CML
1.0
0.9
0.8
0.7
Fraction of patients
that responded
0.6
0.5
0.4
Gleevec™: Rapid Hematologic and Cytogenetic Response1
More than 50% of patients with MCR achieved their response within 3 months (median = 2.9 months) in chronic phase CML. In accelerated phase and blast crisis phase CML, similar results were obtained.
The median time to a hematologic response was 1 month, with a range of 0.9 to 9.3 months in the accelerated phase CML. The median time to a hematologic response was also 1 month for the other phases of CML.
Reference
1. Data on file. Novartis Pharmaceuticals Corporation, East Hanover, NJ.
0.3
0.2
0.1
0.0 1 2 3 4 5 6 7 8 9 10
Months Since Start of Treatment
Data: Novartis Pharmaceuticals Corporation

73. This is an awesome drug!
Patients who achieve a stable cytogenetic response have overall survival rates of 95.2% after 8 years, similar to the rate in the general population. Only 1% of patients died because of leukemia progression
Gleevec™: Rapid Hematologic and Cytogenetic Response1
More than 50% of patients with MCR achieved their response within 3 months (median = 2.9 months) in chronic phase CML. In accelerated phase and blast crisis phase CML, similar results were obtained.
The median time to a hematologic response was 1 month, with a range of 0.9 to 9.3 months in the accelerated phase CML. The median time to a hematologic response was also 1 month for the other phases of CML.
Reference
1. Data on file. Novartis Pharmaceuticals Corporation, East Hanover, NJ.
Journal of the National Cancer Institute 103 (7): 553–561 (2011)

74. Of course there are side effects...
Drug was discontinued for adverse events
in 1% of patients in chronic phase,
2% in accelerated phase,
and 5% in blast crisis

75. Started at $30,000-50,000/year And rose from there
And the cost.....
Started at $30,000-50,000/year
And rose from there
Now >75,000/year!!
BUT it lost patent protection
and became generic in 4 January 2015

76. Generic imatinib is $8000/year In Canada and $400/year in India!
And the cost.....
Generic imatinib is $8000/year
In Canada and
$400/year in India!

77. BUT it loses patent protection
and becomes generic in 2014

78. And that’s not the only problem...

79. 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 UCLA’s Jonsson Cancer Center. In patients
with newly diagnosed disease, we are seeing
resistance to imatinib in about 4%of patients per year.
The further the disease has progressed before
initiating imatinib treatment,
the greater the chances are that resistance will arise.”

80. Unfortunately, natural selection is
a powerful process
About 17% of all patients
develop resistance in 5 years
Science 331: March

81. A possible solution: a new generation of kinase inhibitors that
Still inhibit Gleevec-resistant tumors
aka Dasatinib
Inject Luciferase-expressing tumor cells
Science :

82. Dasatinib FDA approved for patients with relapses
NCI Cancer Bulletin October 5, 2006
aka Dasatinib
Inject Luciferase-expressing tumor cells

83. Dasatinib FDA approved for patients with relapses
NCI Cancer Bulletin October 5, 2006
Leads to 73% progression free survival for 3 years

84. 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
Phase II trials suggest Dasatinib effective in ALL patients
with Gleevec-resistant tumors
NCI Cancer Bulletin May

85. This is becoming a general approach
Science 331: March

86. How much do you think that costs?

87. For CML Add another $70,000/year!

88. 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

89. 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 (<10% response)
Only can be effectively treated if the entire tumor
Can be removed surgically
Without this median survival 1-2 yrs

90. 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 Research –3038,
October 2002

91. Gleevec treatment also reduces risk or recurrence
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

92. Gleevecxtends median survival
GIST
Gleevecxtends median survival
from 15 months to 5 years

93. But.....
Long term outcome ?
Many patients who initially respond develop
secondary resistance to Gleevec and relapse
Cause: second site mutations in c-kit!

94. 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:

95. 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