Hemato-Oncology: From Concept to Cure
HEMATO-ONCOLOGY: FROM
CONCEPT TO CURE
Minor 18
Opleiding: Bachelor biomedische wetenschappen
Onderwijsinstelling: Radboud
1
, Hemato-Oncology: From Concept to Cure
Index
Stem Cell Biology, Clonal Evolution, Pathogenesis and Leukemic Transformation.............................4
Stem Cell Biology...................................................................................................................................................4
Leukemic transformation......................................................................................................................................4
Apoptosis...............................................................................................................................................................5
DNA methylation...................................................................................................................................................6
Ubiquitination........................................................................................................................................................6
Example p53....................................................................................................................................................7
Acute Myeloid Leukemia...................................................................................................................7
Pathogenesis.........................................................................................................................................................7
Clinical presentation..............................................................................................................................................7
Diagnosis................................................................................................................................................................8
Diagnostics.............................................................................................................................................................9
Flow cytometry................................................................................................................................................9
Cytogenetics..................................................................................................................................................10
Treatment......................................................................................................................................................10
Autologous transplantation..........................................................................................................................12
Allogeneic transplantation............................................................................................................................12
Myelo Proliferative Diseases...........................................................................................................15
Chronic myeloid leukemia...................................................................................................................................16
Clinical presentation of CML.........................................................................................................................16
Essential thrombocythemia (ET).........................................................................................................................17
Symptoms......................................................................................................................................................17
Treatment......................................................................................................................................................17
Polycythemia vera...............................................................................................................................................17
Symptoms......................................................................................................................................................17
Treatment......................................................................................................................................................17
Primary myelofibrosis..........................................................................................................................................17
Symptoms......................................................................................................................................................18
Treatment......................................................................................................................................................18
B-cell development..........................................................................................................................19
Lymphoma.......................................................................................................................................20
Diagnostics..........................................................................................................................................................20
Pathology.......................................................................................................................................................21
2
, Hemato-Oncology: From Concept to Cure
Ann Arbor staging..........................................................................................................................................21
Follicular lymphoma............................................................................................................................................21
Pathogenesis.................................................................................................................................................21
Diagnosis.......................................................................................................................................................21
Disease course...............................................................................................................................................22
Therapeutic options......................................................................................................................................22
Diffuse Large B-cell Lymphoma (DLBCL)..............................................................................................................22
Pathogenesis.................................................................................................................................................22
Diagnosis.......................................................................................................................................................23
Disease course...............................................................................................................................................23
Therapeutic options......................................................................................................................................23
Plasma Cell Dyscrasia – Multiple myeloma......................................................................................24
Pathogenesis.......................................................................................................................................................24
Symptoms............................................................................................................................................................24
Diagnose..............................................................................................................................................................25
Immunology..................................................................................................................................................25
Risk assessment.............................................................................................................................................27
Treatment............................................................................................................................................................27
Appendix.........................................................................................................................................29
IVT – GVT Allogeneic stem cell transplantation..................................................................................................29
IVT – GVT Stem cell biology, clonal evolution, pathogenesis and leukemic transformation.............................31
IVT – GVT Acute Myeloid Leukemia – Diagnostics (flow cytometry)..................................................................33
IVT – GVT Allogeneic stem cell transplantation - Immunology and GVHD.........................................................35
IVT – GVT Cellular Immunotherapy – T-cells, Dendritic Cells and NK-cells.........................................................36
IVT – GVT Chronic Myeloid leukemia and primary Myelofibrosis – Clinical aspects and diagnostics................38
IVT – GVT Essential Thrombocytosis and Polycythaemia Vera and secondary myelofibrosis............................40
Formative exam AML and MPN..........................................................................................................................42
IVT – GVT Lymphoma & PDC – Clinical aspects...................................................................................................45
IVT – GVT Lymphoma & PDC – Therapeutic options...........................................................................................47
Formative exam lymphoma and plasma cell dyscrasia.......................................................................................49
3
, Hemato-Oncology: From Concept to Cure
Stem Cell Biology, Clonal Evolution, Pathogenesis and Leukemic Transformation
Stem Cell Biology
Blood cells are divided into three major groups:
Red blood cells (erythrocytes), which provide oxygen transport. A deficiency of red blood cells leads to
anemia.
White blood cells (leukocytes), which are responsible for defense against infections. These are divided
into five types, each with its own name and function. Each species has great variation in terms of
percentage and numbers:
basophilic granulocytes <1%
eosinophilic granulocytes 1-6%;
neutrophilic granulocytes 40-75%
lymphocytes 20-40%
monocytes 2-10%.
Platelets (thrombocytes), responsible for primary hemostasis or blood clotting
During their maturation, hematopoietic
cells express proteins on their cell
membrane (so-called CD markers) the
composition of these proteins depends on
the developmental stage the cell is in.
Hematopoietic stem cells express the
surface molecule CD34 on their cell
membrane. Matured blood cells are CD34
negative.
Characteristic of B cells is the expression of
CD20 on the cell membrane. T cells,
however, express CD4 and CD8.
Pleitropic growth factors: these are factors aimed at differentiation and already act on precursor or progenitor
cells, such as IL-3, for example.
Lineage-specific growth factors: are factors aimed at maturation, they
act on the more mature cells, such as G-CSF on neutrophilic
granulocytes and basophilic granulocytes and Epo on erythrocytes.
Leukemia results from the uncontrolled accumulation of primitive,
poorly differentiated blood cells, and is a consequence of the
accumulation of mutations in hematopoietic precursor cells. It seems
likely that mutations affecting at least two pathways are required for
the development of leukemia. One of these pathways regulates cell
accumulation; the second regulates hematopoietic differentiation.
Genes that are mutated in leukemia can be classified in four major biological groups:
Growth factor receptors
Signal transduction molecules
Gene expression regulation
Apoptosis
Leukemic transformation
Random mutations occur in our genome for instance by toxic agents, UV and mistakes in copying DNA during
cell division. Most of these mutations are biologically inactive and not harmful. Still they are passed on to all
daughter cells. These mutations are called passenger mutations. When, however a mutation occurs in a gene
that regulates the balance between proliferation and differentiation, the cell may acquire a growth advantage
leading to the expansion of a clone that harbors the mutation. These mutations are called driver mutations.
4
HEMATO-ONCOLOGY: FROM
CONCEPT TO CURE
Minor 18
Opleiding: Bachelor biomedische wetenschappen
Onderwijsinstelling: Radboud
1
, Hemato-Oncology: From Concept to Cure
Index
Stem Cell Biology, Clonal Evolution, Pathogenesis and Leukemic Transformation.............................4
Stem Cell Biology...................................................................................................................................................4
Leukemic transformation......................................................................................................................................4
Apoptosis...............................................................................................................................................................5
DNA methylation...................................................................................................................................................6
Ubiquitination........................................................................................................................................................6
Example p53....................................................................................................................................................7
Acute Myeloid Leukemia...................................................................................................................7
Pathogenesis.........................................................................................................................................................7
Clinical presentation..............................................................................................................................................7
Diagnosis................................................................................................................................................................8
Diagnostics.............................................................................................................................................................9
Flow cytometry................................................................................................................................................9
Cytogenetics..................................................................................................................................................10
Treatment......................................................................................................................................................10
Autologous transplantation..........................................................................................................................12
Allogeneic transplantation............................................................................................................................12
Myelo Proliferative Diseases...........................................................................................................15
Chronic myeloid leukemia...................................................................................................................................16
Clinical presentation of CML.........................................................................................................................16
Essential thrombocythemia (ET).........................................................................................................................17
Symptoms......................................................................................................................................................17
Treatment......................................................................................................................................................17
Polycythemia vera...............................................................................................................................................17
Symptoms......................................................................................................................................................17
Treatment......................................................................................................................................................17
Primary myelofibrosis..........................................................................................................................................17
Symptoms......................................................................................................................................................18
Treatment......................................................................................................................................................18
B-cell development..........................................................................................................................19
Lymphoma.......................................................................................................................................20
Diagnostics..........................................................................................................................................................20
Pathology.......................................................................................................................................................21
2
, Hemato-Oncology: From Concept to Cure
Ann Arbor staging..........................................................................................................................................21
Follicular lymphoma............................................................................................................................................21
Pathogenesis.................................................................................................................................................21
Diagnosis.......................................................................................................................................................21
Disease course...............................................................................................................................................22
Therapeutic options......................................................................................................................................22
Diffuse Large B-cell Lymphoma (DLBCL)..............................................................................................................22
Pathogenesis.................................................................................................................................................22
Diagnosis.......................................................................................................................................................23
Disease course...............................................................................................................................................23
Therapeutic options......................................................................................................................................23
Plasma Cell Dyscrasia – Multiple myeloma......................................................................................24
Pathogenesis.......................................................................................................................................................24
Symptoms............................................................................................................................................................24
Diagnose..............................................................................................................................................................25
Immunology..................................................................................................................................................25
Risk assessment.............................................................................................................................................27
Treatment............................................................................................................................................................27
Appendix.........................................................................................................................................29
IVT – GVT Allogeneic stem cell transplantation..................................................................................................29
IVT – GVT Stem cell biology, clonal evolution, pathogenesis and leukemic transformation.............................31
IVT – GVT Acute Myeloid Leukemia – Diagnostics (flow cytometry)..................................................................33
IVT – GVT Allogeneic stem cell transplantation - Immunology and GVHD.........................................................35
IVT – GVT Cellular Immunotherapy – T-cells, Dendritic Cells and NK-cells.........................................................36
IVT – GVT Chronic Myeloid leukemia and primary Myelofibrosis – Clinical aspects and diagnostics................38
IVT – GVT Essential Thrombocytosis and Polycythaemia Vera and secondary myelofibrosis............................40
Formative exam AML and MPN..........................................................................................................................42
IVT – GVT Lymphoma & PDC – Clinical aspects...................................................................................................45
IVT – GVT Lymphoma & PDC – Therapeutic options...........................................................................................47
Formative exam lymphoma and plasma cell dyscrasia.......................................................................................49
3
, Hemato-Oncology: From Concept to Cure
Stem Cell Biology, Clonal Evolution, Pathogenesis and Leukemic Transformation
Stem Cell Biology
Blood cells are divided into three major groups:
Red blood cells (erythrocytes), which provide oxygen transport. A deficiency of red blood cells leads to
anemia.
White blood cells (leukocytes), which are responsible for defense against infections. These are divided
into five types, each with its own name and function. Each species has great variation in terms of
percentage and numbers:
basophilic granulocytes <1%
eosinophilic granulocytes 1-6%;
neutrophilic granulocytes 40-75%
lymphocytes 20-40%
monocytes 2-10%.
Platelets (thrombocytes), responsible for primary hemostasis or blood clotting
During their maturation, hematopoietic
cells express proteins on their cell
membrane (so-called CD markers) the
composition of these proteins depends on
the developmental stage the cell is in.
Hematopoietic stem cells express the
surface molecule CD34 on their cell
membrane. Matured blood cells are CD34
negative.
Characteristic of B cells is the expression of
CD20 on the cell membrane. T cells,
however, express CD4 and CD8.
Pleitropic growth factors: these are factors aimed at differentiation and already act on precursor or progenitor
cells, such as IL-3, for example.
Lineage-specific growth factors: are factors aimed at maturation, they
act on the more mature cells, such as G-CSF on neutrophilic
granulocytes and basophilic granulocytes and Epo on erythrocytes.
Leukemia results from the uncontrolled accumulation of primitive,
poorly differentiated blood cells, and is a consequence of the
accumulation of mutations in hematopoietic precursor cells. It seems
likely that mutations affecting at least two pathways are required for
the development of leukemia. One of these pathways regulates cell
accumulation; the second regulates hematopoietic differentiation.
Genes that are mutated in leukemia can be classified in four major biological groups:
Growth factor receptors
Signal transduction molecules
Gene expression regulation
Apoptosis
Leukemic transformation
Random mutations occur in our genome for instance by toxic agents, UV and mistakes in copying DNA during
cell division. Most of these mutations are biologically inactive and not harmful. Still they are passed on to all
daughter cells. These mutations are called passenger mutations. When, however a mutation occurs in a gene
that regulates the balance between proliferation and differentiation, the cell may acquire a growth advantage
leading to the expansion of a clone that harbors the mutation. These mutations are called driver mutations.
4
