STEM CELL BIOLOGY
NORMAL HAEMATOPOIESIS
haematopoiesis = formation of blood in the bone marrow
hematopoietic stem cell:
o very low numbers
o quiescent dividing once or twice a year
o present during a full lifetime
o present deep in the bone marrow & divide rarely protected against mutations
recognizing blood cell populations:
o CD34+, CD38-, Thy1+, c-Kit+, IL-3R-
o CD38+ after the first division
o antibody conjugated to a fluorochrome
binding a specific marker
o SCs can’t just be identified by cell
surface markers, only populations can
be identified
specific cell transplantations in mice:
o nucleated cells (effector cells) into
immunodeficient mice short lifespan
o SCs all blood lineages (myeloid and
lymphoid) develop after 9 months
transplantation/reconstitution with 1 cell
,LEUKAEMIA DEVELOPMENT
disbalance proliferation/differentiation/apoptosis caused by genetic mutations
>20% undifferentiated cells in the bone marrow
myeloid vs. lymphoid
acute (rapid increase) vs. chronic (slower growing disease)
early days morphological classification nowadays genetic classification
symptoms: fatigue, fever, anaemia, swollen lymph nodes, night sweats, pain in joints and
bones, loss of weight, bleeding tendency, enlarged spleen, kidney, and the liver, bone
tenderness very general complaints
treatment:
o 2 courses of very intensive chemotherapy + a final course if the patient can take it
o subtype specific treatments (rare)
o mostly allogeneic transplantation, autologous are rarer
cell of origin:
, o multiple mutations and multiple disrupted pathways needed for leukaemia to arise
o possible in short-term SC if there is a mutation in the self-renewal machine
o mutations in the early SC stay present due to self-renewal potential
leukaemia cell populations:
o leukemic stem cell (LSC) quiescent
o leukemic cells proliferative
o leukemic blasts proliferative, cause the disease the phenotype since they push
away the normal cells from the bone marrow
o resembles normal population
o can expand but not differentiate
transplantation models:
o only blasts transplanted into mice hardly any formation of leukaemia
o LSC often leukaemia, can arise from 1 cell
o several types not transplantable since they are often dependent on the surrounding
microenvironment
cell of origin vs. cancer stem cells:
o CD38- = cell of origin, pre-malignant cell where the first mutation takes place
o CD38+ = leukaemia-initiating SC, continuous generation of more differentiated
immature leukaemia blasts doesn’t imply that it is directly derived from normal
SC, it can also be derived from a more mature cell
o GF independent, disrupted apoptosis, differentiation block
TARGETED THERAPY
conventional chemotherapy kills fast dividing cells, but LSCs not targeted and they can
persist targeted therapy for all malignant cells
studying which mutation comes first, their effect, and targeting them
very specific, less toxic, and less side effects
resistance, relevant target required, expensive, not for all patients
some mutations don’t disappear after cure pre-LSCs can still persist, but it does not mean
the patient has leukaemia, so they are not treated
DNMT3A mutation
CLONAL EVOLUTION IN CANCER
MUTATIONS & HAEMATOPOIESIS
biological routes involved in normal cell growth:
o receptors activated by signalling molecules (GF) gene messaging, survival,
apoptosis nucleus
o unbalanced signals disturbance of growth control apoptosis activation
o genes mutated in leukaemia:
GF receptors
signal transduction molecules
gene expression regulation: TFs, epigenetic regulators, RNA splicing factors,
chromatin organization
apoptosis
NORMAL HAEMATOPOIESIS
haematopoiesis = formation of blood in the bone marrow
hematopoietic stem cell:
o very low numbers
o quiescent dividing once or twice a year
o present during a full lifetime
o present deep in the bone marrow & divide rarely protected against mutations
recognizing blood cell populations:
o CD34+, CD38-, Thy1+, c-Kit+, IL-3R-
o CD38+ after the first division
o antibody conjugated to a fluorochrome
binding a specific marker
o SCs can’t just be identified by cell
surface markers, only populations can
be identified
specific cell transplantations in mice:
o nucleated cells (effector cells) into
immunodeficient mice short lifespan
o SCs all blood lineages (myeloid and
lymphoid) develop after 9 months
transplantation/reconstitution with 1 cell
,LEUKAEMIA DEVELOPMENT
disbalance proliferation/differentiation/apoptosis caused by genetic mutations
>20% undifferentiated cells in the bone marrow
myeloid vs. lymphoid
acute (rapid increase) vs. chronic (slower growing disease)
early days morphological classification nowadays genetic classification
symptoms: fatigue, fever, anaemia, swollen lymph nodes, night sweats, pain in joints and
bones, loss of weight, bleeding tendency, enlarged spleen, kidney, and the liver, bone
tenderness very general complaints
treatment:
o 2 courses of very intensive chemotherapy + a final course if the patient can take it
o subtype specific treatments (rare)
o mostly allogeneic transplantation, autologous are rarer
cell of origin:
, o multiple mutations and multiple disrupted pathways needed for leukaemia to arise
o possible in short-term SC if there is a mutation in the self-renewal machine
o mutations in the early SC stay present due to self-renewal potential
leukaemia cell populations:
o leukemic stem cell (LSC) quiescent
o leukemic cells proliferative
o leukemic blasts proliferative, cause the disease the phenotype since they push
away the normal cells from the bone marrow
o resembles normal population
o can expand but not differentiate
transplantation models:
o only blasts transplanted into mice hardly any formation of leukaemia
o LSC often leukaemia, can arise from 1 cell
o several types not transplantable since they are often dependent on the surrounding
microenvironment
cell of origin vs. cancer stem cells:
o CD38- = cell of origin, pre-malignant cell where the first mutation takes place
o CD38+ = leukaemia-initiating SC, continuous generation of more differentiated
immature leukaemia blasts doesn’t imply that it is directly derived from normal
SC, it can also be derived from a more mature cell
o GF independent, disrupted apoptosis, differentiation block
TARGETED THERAPY
conventional chemotherapy kills fast dividing cells, but LSCs not targeted and they can
persist targeted therapy for all malignant cells
studying which mutation comes first, their effect, and targeting them
very specific, less toxic, and less side effects
resistance, relevant target required, expensive, not for all patients
some mutations don’t disappear after cure pre-LSCs can still persist, but it does not mean
the patient has leukaemia, so they are not treated
DNMT3A mutation
CLONAL EVOLUTION IN CANCER
MUTATIONS & HAEMATOPOIESIS
biological routes involved in normal cell growth:
o receptors activated by signalling molecules (GF) gene messaging, survival,
apoptosis nucleus
o unbalanced signals disturbance of growth control apoptosis activation
o genes mutated in leukaemia:
GF receptors
signal transduction molecules
gene expression regulation: TFs, epigenetic regulators, RNA splicing factors,
chromatin organization
apoptosis
