L2: Haematological cancer part 2 Flashcards
leukemias
Leukemias
Acute myeloid leukaemia
Chronic myeloid leukaemia
Acute lymphoblastic leukaemia
Chronic lymphocytic leukaemia
Myeloid haematological cancers
Malignancies effecting the myeloid lineage. Lots of intermediate steps to form the fully differentiated cell types. Genetic changes are within these stages of the cells that are undergoing differentiation.
Acute myeloid leukemia (AML)
Mostly occurs in adults with median age of 67 at onset
Symptoms reflect massive accumulation in the bone marrow of immature myeloid cells that cannot differentiate. Overwhelms the marrow and prevents normal haematopoiesis.
Diagnosis: 20% or more blasts (immature cells with high nuclear to cytoplasmic ratio) in blood or bone marrow. Normal haematopoesis is not occuring in these patients.
High nuclear to cytoplasmic ratio. Blast.
As it is leukemia cells circulate.
To diagnose patients look at..
Morphology and phenotype used to define lineage affected
Cytogenetic and molecular analysis for definitive diagnosis of AML type
Chemotherapy induces remission in most patients, but relapse rates are high and 5-year survival rate is <30%
Allogeneic haematopoietic stem cell transplantation is a common treatment - only curative therapy.
genetic abnormalities
Multiple genetic changes can lead to AML.
In addition to chromosomal translocations, patients will have point mutations. Most frequent genes- FLT3? NPM1? DMNTA?
Common features shared but patients usually have a ynique combination of chromosomal abnormalities and mutated genes.
APL?
Acute promyelocytic leukemia (APL): has very good prognosis ( a highly treatable form of aml)
t(15;17) reciprocal translocation in which PML gene on chromosome 15 is fused to retinoic acid receptor α (RARa) gene on chromosome 17
PML-RARa fusion protein fails to respond to normal levels of retinoic acid
The two genes fuse and form a fusion gene. pml on chromosome 15 fuses with retanoic acid receptor alpha gene on chromosome 17. Chromosmal translocation will not form a mature? Protein. The retanoic acid portion when linked to pml will not function. Cannot respond to normal levels of retanoic acid. Accumulation of promyelocyic cells accumulate in blood due to arrested differentiation.
Treatment: high dose of retanoic acid overcomes defect and drives differentiation. Pushes undifferentiated cells that accumulated to fully differentiate.
5 year survival rate >80%
allogenic haematopoietic stem cell transplantation
Allogenic haematopoetic stem cell transplantation (HSCT)
When feasible (most patients are not eligible. Disease may be too advanced, comorbities, older people?, allogenic- has to come from suitable healthy donor) allogeneic HSCT is treatment of choice for most AML types
Clinical HSCT has been done for >50 years with >one million HSC transplants performed
Chemotherapy / radiotherapy to destroy leukaemic cells followed by infusion of stem cells from a healthy donor (allogeneic) that regenerates haematopoietic cell types
Treatment related problems are susceptibility to infections and graft versus host disease
bone marrow aspirate from ilac crest of conor or leukapheresis of stem cells from peripheral blood after g-csf injection—>
donor stem cells infused intravenously
given to patient: intensive support therapy- red cell and platlet transfusion, antibiotics, GvHD prophytaxis
*look at this image
About 50% with aml who get a transplant are cured.
Treatment-related problems, patients have increased risk of infection and gvhd
chronic myeloid leukemia
Chronic myeloid leukemia (CML)
Affects pluripotent haematopoietic stem cell
Accounts for 15% leukaemias and can occur at any age
White blood cell count >200x109/L (normal 4-11x109/L)
Huge abnormal numbers of white blood cells. Cml blasts- immature progenitors fill up.
Hypercellular bone marrow filled with myeloid progenitors at various stages of differentiation
Circulating in blood but also in bone marrow.
Blast cells filling up space in the bone marrow.
Dark pink- indicates myeloid lineage. Characteristic granules.
Numerous granulocytes at various stages of development
Characterised by presence of truncated chromosome 22 known as the Philadelphia (Ph) chromosome formed by a reciprocal translocation between chromosome 9 and 22
BCR-ABL fusion protein
BCR-ABL fusion protein
Part of tyrosine kinase ABL1 oncogene on chromosome 9 moved to breakpoint cluster region (BCR) gene on chromosome 22 and part of chromosome 22 moved to chromosome 9
Creates a BCR-ABL fusion gene
ABL: 145 kDa non-receptor tyrosine kinase mainly present in nucleus
BCR: 160 kDa cytoplasmic ser/thr kinase
BCR-ABL fusion product: 210 kDa cytoplasmic has enhanced tyrosine kinase activity. Fusion protein is functional. But tyrosine kinase activity of abl is expressed at high levels in the cytoplasm.
Consequence is increased phosphorylation of tyrosine residues on cytoplasmic signalling proteins which promotes increased cell proliferation and the malignant phenotype
CML treatment
BCR-ABL fusion protein
Part of tyrosine kinase ABL1 oncogene on chromosome 9 moved to breakpoint cluster region (BCR) gene on chromosome 22 and part of chromosome 22 moved to chromosome 9
Creates a BCR-ABL fusion gene
ABL: 145 kDa non-receptor tyrosine kinase mainly present in nucleus
BCR: 160 kDa cytoplasmic ser/thr kinase
BCR-ABL fusion product: 210 kDa cytoplasmic has enhanced tyrosine kinase activity. Fusion protein is functional. But tyrosine kinase activity of abl is expressed at high levels in the cytoplasm.
Consequence is increased phosphorylation of tyrosine residues on cytoplasmic signalling proteins which promotes increased cell proliferation and the malignant phenotype
(bcr-abl) substrate e.g: grb-2, shc
acute lymphoblastic leukemia
Incidence highest at 3-7 years
The most common cancer of childhood
Proliferation of lymphoid blasts
85% of cases affect B-cell lineage but can also occur in T cells
Lymphocytes: nk, b cells, t cells. Acute lymphoblastic leukemia mostly affect b cell lineage but sometimes in t cell lineage.
Treatments include conventional chemotherapy, allogeneic haematopoietic stem cell transplantation and novel chimeric antigen receptor (CAR) T cells
5-year survival rate 90% in children, 30-40% in adults
Quite a few genetic abnormalities involve chromosomal translocation?
B-ALL treatment with CAR T cells
B-ALL treatment with CAR T cells
Genetic modification of T cells to express a chimeric antigen receptor (CAR)
Antigen specificity conferred by variable region of an antibody (scFv) linked to T cell receptor signaling sequences
For B-ALL, antibody targets B-cell specific CD19 or CD20 molecules
Approved for use in B-ALL when other treatments fail
Response rates up to 90%
Problems are B-cell deficiency, toxicities, disease relapse and high cost
CARs: scFv, hinge, transmembrane domain, costimulatory domain (CD28, 4-1BB, CD3
single protein, high adjustable affinity, recognition is mhc-independent (broader applicability
y)
Chimeria- immunoglobulin antibody recognition domain linked to signalling components required to activate t cells
Cd19 and cd20- only expressed on b cells.
Target car t cells to b cells by having ab that recognises cd19 or cd20. Brings car t to b cells. When ab engages with cd19 or cd2- triggers car t cells to kill b cells?
chronic lymphocytic leukemia (CLL)
Occurs predominantly in older adults
Usually identified incidentally with raised white blood cell count and asymptomatic
Increased B (or T) lymphocytes in both blood and bone marrow due to a clonal expansion
Early stages require no treatment
Many new first line treatment options at symptomatic stage have substantially improved prognosis inducing remission, but not cure
CLL genetics
High mutational heterogeneity
2000-3000 mutations per patient (mostly passenger mutations)
Four common chromosomal changes
deletion 13q14
trisomy 12
deletion at 11q23 (involves ATM gene)
17p deletion (involves TP53 gene)
Common driver somatic mutations in ATM, NOTCH1, SF3B1, TP53
Novel treatments of CLL
Bruton tyrosine kinase (BTK) inhibitors: Example ibrutinib
BCL-2 inhibitors: Example Venetoclax
Monoclonal antibodies: Example anti-CD20 Rituximab
Cytolytic monoclonal antibody targeting
Inhibit B cell receptor (Ig) pro-survival signals: BTK inhibitors
Inhibit mitochondrial pro-survival signals: BCL2 inhibitors
Tyrosine kinase inhibitors block the survival signals (anti-apoptotic signals)
