Haematological Malignancies (2) Flashcards
what is the normal WBC count?
~11
How does Chronic myeloid leukaemia occur?
c-ABL located on chromosome 9 is translocated to breakpoints on chromosome 22 in clustered relatively small region (BCR)
What does BCR-Abl induce?
Stronger tyrosine kinase activity
How do leukaemic cells induce cell division and proliferation?
Intregins are expressed on leukaemic cells -> Binds to stromal cells -> Stops normal cell division -> Integrins detach but leukaemic cells are still attached to stromal cells -> cell division and proliferation
What is the tyrosine kinase activity in BCR-Abl important for?
To be able to transform cells
What drug targets Abl and BCR-Abl?
Imatinib
What else does Imatinib target?
Tel-Abl
PDGFR
KIT
How does Imatinib work in CML?
It binds to the ATP binding pocket
BCR-Abl require the binding pocket to convert ATP to ADP and therefore phosphorylate the tyrosine kinase motif to activate BCR-Abl
How many people who have bone marrow transplants die due to treatment?
~20-30%
How long can symptoms of CML take? And why?
5 years due to the removal of the bone marrow
What is the survival rate at 10 years using imatinib?
83.3%
What factors can you monitor to see if a patient is improving with imatinib?
Blood count (haematological) Philadelphia chromosome (cytogenetic) BCR-Abl1 level (molecular level)
What is a complete response?
If you cannot detect any BCR-Abl
How do you predict if someone has a complete response and their life expectancy wont change?
Their blood count is restored
The philadelphia chromosome has been removed
BCR-Abl has been removed
What is a long term side effect of imatinib?
Fluid accumulation in the lungs (take take 3 years to present) - causes breathlessness
What are the side effects of imatinib?
Hemorrhage Edema Nausea and vomiting Low blood count Fever Diarrhea Skin rash Muscle cramps and bone pain Vascular obstruction Pleural effusion Pulmonary hypertension
What are the issue with imatinib?
Toxicity
Sub-optimal response
Disease re-emergence
Due to the issues with imatinib, what have been developed?
Second generation drugs
Give some examples of second generation drugs
Nilotinib
Dasatinib
Ponatinib
How does resistance typically occur to imatinib?
due to mutations in the ATP binding site which imatinib binds to
What is the best second generation drug and why?
Ponatinib
T315 mutations in CML - this drug is still able to bind
Name a rare subset of AML
Acute promyelocytic leukaemia (APL)
How many patients die at presentation of APL?
30%
What is one of the main issue with APL?
Commonly get brain bleeds
How is APL characterised?
By blood coagulation abnormalities
What chromosomes are associated with APL?
Chromosome 15 and 17
What gene is on chromosome 15?
PML
what gene is on chromosome 17?
RARalpha
What chromosome is formed in APL patients?
PML-RARalpha
What does chemotherapy do to APL patients?
Increased bleeding and increases risk of early death
What is the treatment for APL patients?
Vitamin A analogue, retinoic acid
What is RARalpha?
A nucleur hormone receptor
What does RARalpha form a heterodimer with?
Retinoid X Receptor (RXR)
What does RARalpha/RXR bind?
Retinoic acid response elements (RAREs) in the promoter region of genes, including those regulating myeloid differentiation
What silences genes?
DNA methyltransferases Histone deacetylases (HDAC)
What increases gene activity?
Histone acetyltransferases (HAT)
What normally happens in the absence of retinoic acid?
RARalpha-RXR heterodimer recruits corepressors, including HDACs -> silence target gene expression
What normally happens in the presence of retinoic acid?
RARalpha binds to retinoic acid -> conformational change in the RARalpha/RXR heterodimer -> release of the nucleur co-repressors and recruit coactivators -> increase gene expression
What happens in PML-RARalpha?
It cannot response to physiological conditions of retinoic acid -> represses gene transcription -> causes t to stay as a primitive cell
What are the effects of PML-RARalpha?
Alters the epigenetic landscape through histone deacetylation
Affects transcription of genes controlled by other nuclear factors
Stimulates the transcription of hypoxia-induced factors (pro-angiogenesis)
suppresses PML-nuclear body and p53 responses
What is the effect of pharmacological all trans retinoic acid (ATRA) on APL?
Overcomes the suppressive effects of protein PML-RARalpha
Recruits histone demethylase
May involve proteolytic degradation of PML-RARalpha
Differentiation of leukaemic cells into mature granulocytes -> growth of normal bone marrow
What is ATRA effective with?
chemotherapy
What is the clinical outcome of APL?
90% remission and a high rate of cure with combined ATRA and reduced intensity chemotherapy
What chemotherapy is used with ATRA?
Arsenic trioxide
How does arsenic trioxide work?
Increases ROS -> Disulphide links in PML or PML-RARalpha and binding to arsenic -> forms nuclear matrix associated nuclear bodies by disulphide-linked multimers -> Sumoylation and degradation of PML-RARalpha
Can induce molecular remission
What is the survival rate of ATRA and Arsenic trioxide?
97% at 5 years
What are Bispecific T cell engager antibodies?
They have dual specificity for tumour antigen and CD3
Functionally replace the MHCI/peptide/TCR complex
