LE Stem cell biology
Oncogenic transcription factor (mutation)
Cure rate 40%
State-of-the-art combination therapy
o Retinoic acid (vitamin A) and arsenic trioxide (=rat poison)
o Both bind oncogenic transcription factor > proteasomal degradation
o Differentiation of leukemia cells, apoptosis
Cure rate now > 95%
Understanding disease pathogenesis and cells that are involved
Normal hematopoiesis
Hematopoiesis takes place in the bone marrow
Stem cells: quiescent
Present during a full lifetime
Protected against mutations
o mutations occur during cell division, in bone marrow is protected
environment (no toxins, UV and are capsuled in)
1 cell division every 25-50 weeks (produces millions of red blood cells)
Recognizing blood cell populations / The hematopoietic stem cell
CD34+ and CD38+ (hematopoietic stem cell markers) after first division
Characterization with Flow cytometry
The stem cell cannot be identified with just cell surface markers
Can only identify populations
, Specific cell transplantations in mice
o Implanting stem cells
Long term hematopoiesis (>9 months)
Contribution to all blood lineages
Transplantation / reconstitution with 1 cell
Development of leukemia
Clinical symptoms and treatment of leukemia
Disbalance proliferation/differentiation/apoptosis caused by genetic
mutations
>20% immature cells in bone marrow
Myoloid vs lymphoid
Acute vs chronic
Classification of subtypes
o Morphological classification (M0-M7)
Which differentiation state (M7 is more mature, M0 is not
mature)
o Includes genetic classification
Treatment aimed at cure (leukemia)
o 2 courses of very intensive chemotherapy
When having bad prognosis 3 courses can be given
o AML subtype specific treatment regimes
o Autologous transplantation / allogeneic transplantation (dependent
on fitness of patient) > dependent on subtype of leukemia
Cut off age 65 years
Cure rate below 60 = 40%
Cure rate above 60 = 10%
What is the cell of origin
Increased cell division > chance genetic mutations > cells: > chance
something goes wrong
Limited self-renewal and differentiation: cell disappears
, Gains back potential to have indefenate self-renewal > form leukemia
Leads to more formation of leukemia
Cell will not get cleaned up because is stem cell, so it has more potential to
proliferate
Leukemia also consists of different cell populations
Transplantation models
Putting them in mice
o Blasts > hardly formation of leukemia
o LSC > often leukemia
, Leukemia can arise from 1 cell
o Several type of leukemia not transplantable
The cell of origin vs cancer stem cells
Cell that has gained first mutation = cell of origin
Does not have to form cancer, because it only has one mutation, so the
divided cell of these cell are probably the cancer cells (these could have an
extra mutations and therefore develop cancer)
Example
Specific type of AML that have a chromosomal fusion that can drive
leukemia formation
o CD34+CD38- cell fraction mutation positive
Leukemia vs normal hematopoiesis
Normal stem cell : generation all mature blood cell types, life long
Cancer stem cell: continuous generation more differentiated immature leukemia
blasts
Does not imply that cancer stem cell is directly derived from normal stem
cell, it can be derived from a more mature cell
Targeted therapy
Conventional chemo: kills fastly dividing cells
Precision therapy:
Leukemia is caused by multiple genetic hits
Oncogenic transcription factor (mutation)
Cure rate 40%
State-of-the-art combination therapy
o Retinoic acid (vitamin A) and arsenic trioxide (=rat poison)
o Both bind oncogenic transcription factor > proteasomal degradation
o Differentiation of leukemia cells, apoptosis
Cure rate now > 95%
Understanding disease pathogenesis and cells that are involved
Normal hematopoiesis
Hematopoiesis takes place in the bone marrow
Stem cells: quiescent
Present during a full lifetime
Protected against mutations
o mutations occur during cell division, in bone marrow is protected
environment (no toxins, UV and are capsuled in)
1 cell division every 25-50 weeks (produces millions of red blood cells)
Recognizing blood cell populations / The hematopoietic stem cell
CD34+ and CD38+ (hematopoietic stem cell markers) after first division
Characterization with Flow cytometry
The stem cell cannot be identified with just cell surface markers
Can only identify populations
, Specific cell transplantations in mice
o Implanting stem cells
Long term hematopoiesis (>9 months)
Contribution to all blood lineages
Transplantation / reconstitution with 1 cell
Development of leukemia
Clinical symptoms and treatment of leukemia
Disbalance proliferation/differentiation/apoptosis caused by genetic
mutations
>20% immature cells in bone marrow
Myoloid vs lymphoid
Acute vs chronic
Classification of subtypes
o Morphological classification (M0-M7)
Which differentiation state (M7 is more mature, M0 is not
mature)
o Includes genetic classification
Treatment aimed at cure (leukemia)
o 2 courses of very intensive chemotherapy
When having bad prognosis 3 courses can be given
o AML subtype specific treatment regimes
o Autologous transplantation / allogeneic transplantation (dependent
on fitness of patient) > dependent on subtype of leukemia
Cut off age 65 years
Cure rate below 60 = 40%
Cure rate above 60 = 10%
What is the cell of origin
Increased cell division > chance genetic mutations > cells: > chance
something goes wrong
Limited self-renewal and differentiation: cell disappears
, Gains back potential to have indefenate self-renewal > form leukemia
Leads to more formation of leukemia
Cell will not get cleaned up because is stem cell, so it has more potential to
proliferate
Leukemia also consists of different cell populations
Transplantation models
Putting them in mice
o Blasts > hardly formation of leukemia
o LSC > often leukemia
, Leukemia can arise from 1 cell
o Several type of leukemia not transplantable
The cell of origin vs cancer stem cells
Cell that has gained first mutation = cell of origin
Does not have to form cancer, because it only has one mutation, so the
divided cell of these cell are probably the cancer cells (these could have an
extra mutations and therefore develop cancer)
Example
Specific type of AML that have a chromosomal fusion that can drive
leukemia formation
o CD34+CD38- cell fraction mutation positive
Leukemia vs normal hematopoiesis
Normal stem cell : generation all mature blood cell types, life long
Cancer stem cell: continuous generation more differentiated immature leukemia
blasts
Does not imply that cancer stem cell is directly derived from normal stem
cell, it can be derived from a more mature cell
Targeted therapy
Conventional chemo: kills fastly dividing cells
Precision therapy:
Leukemia is caused by multiple genetic hits
