Edmead Lec 6 Flashcards
Leukaemia is cancer of the _____. It is due to ____ cells that circulate round the body. When testing for Leukaemia a _____ sample is taken to test for mutations in these cells. These cells originate in the ____ ____ and a ____ ____ aspiration can be taken to test for cancerous cells.
Blood Single Blood Bone marrow Bone marrow
Leukaemia is cancer of the ____ ____ cells. The function of these cells is mutated so patients often become susceptible to infection making them _______. The unregulated _______ of a clone of immature blood cells leads to a variety of different ____ ____ cells and diseases.
White blood cells
Immunosuppressed
Proliferation
White blood cells
WBC and RBC develop from _______ cells (__________) on the stem cell pathway between undifferentiated cells and mature cells. An accumulation of mutation in these ______ cells is likely to give rise to ______ cells which proliferate relentlessly. Proliferation of abnormal WBC crowds out the other normal cells of the bone marrow which suppresses the bone marrow function. Can treat this with a bone marrow ______ but if you leave some cancerous cells behind then these can ______ and leukaemia can return.
Progenitor Haematopoeitic Progenitor Leukaemic Transplant Recolonise
Patients with leukaemia have blood that appears ____ as the WBCs proliferate and are immature.
Milky
________ stem cells can _______ into 3 types of blood cell. What are they?
Myeloid - granulocytes, neutrophils, macrophages, mast cells (Innate immune)
Erythroid - Red blood cells
Lymphoid - T lymphocytes, B lymphocytes (adaptive immune)
Classification of leukaemia:
1) Based on the ____ of the cell e.g. myeloid or l_____ leukaemias
2) Acute/_____. _____ phase usually comes ___ and is a long initiation of the cancer where the cells grow faster and is a sort of _____ phase as pts can survive a relatively long time. The acute phase can occur after an extra mutation and is much more _____ and can lead to death.
____ phase can be accumulation of mutations and Acute phase can be the extra mutation that leads to malignant cell development.
Origin Lymphoid Chronic Chronic 1st Benign Serious Chronic
Chronic myeloid leukaemia:
Is a disease of the ______.
Patients present with: f_____, a_____, s______ (enlarged spleen) and ______ (enlarged liver)
In a blood sample: patients will have an elevated number of ____ in blood count
In a blood smear all the stages of ______ differentiation will be seen . Some will be differentiated and others ____ and blast like. There is a ______ in cells.
A bone marrow sample may show abnormal number of xs cells and increased ratio of ____ to erythroid cells.
Neutrophils Fatigues, anaemia, splenomegaly, hepatomegaly WBC Granulocyte Blast like Heterogeneity Myeloid
Three clinical phases to Chronic myeloid leukaemia:
1) Initial ____ phase: fairly mild and maybe progressing for couple of years before aware
2) ______ phase: probably due to further mutations
3) ____ leukaemia phase: all cells turn into immature WBC that proliferate. They crowd out the ____ _____ and patients often die of _____ - BLAST CRISIS
Chronic Accelerated Acute Bone marrow Infections
Leukaemia is a ________ process. You still need an accumulation of mutations.
_____ is mutated in around ___% of AML cancers
________ abnormalities is common:
e.g. additions, ______, ______ and _____.
These result in the aberrant activation of proteins.
Rather than point mutations.
Multifactorial RAS 50% chromosomal translocations deletions amplifications
Features of CML:
Novel oncogenes found in those with leukaemia were due to early _____ that weren’t detected in _____ cells. These weren’t detected, _____ or killed. They therefore, continued to _____ and pass on the novel oncogenes to daughter cells. So if patients were screened early on you could see if they were predisposed to developing cancer and treat early. But would need to screen everyone.
Mutations
Progenitor
Repaired
Proliferate
CML is due to the overproduction of ______. In CML there is a reciprocal _____ ______ between chromosomes 9 and __. A bit breaks off chromosome 9 and __ and they swap over. This isn’t an issue BUT if the gene translocates from an area of ___ transcription to ____ then this is an issue. E.g BCL2 translocation. BCL2 blocks _____ and is pro_____. It has been identified in B cells and the gene translocates from an area of low expression to an area of high expression next to an ______ promoter. The B cells make lots of _____ and as the BCL2 is next to this promoter they made lots of BCL2 too! This lead to B cell ______. The cells didn’t die by _____ and proliferated.
Neutrophils Chromosomal translocation 22 22 Apoptosis Pro survival Immunoglobulin Antibodies Lymphoma Apoptosis
Breakages and splices that occur during chromosomal translocation occur within ____ rather than between _____. If you move a whole gene you will affect it’s transcription and expression, but moving part of a gene affects the gene ____. In CML, it breaks between 2 genes on each chromosome - the ___ (breakpoint cluster region gene) and the _-___ (___ tyrosine kinase). _-____ is a protooncogene and becomes oncogenic when fused to ___.
Genes Genes Sequence BCR c-ABL ABL c-ABL BCR
Molecular basis of CML:
- Can stain chromosomes to see that 1 copy of chromosome _ elongates and the other copy of chromosome __ gets ____. On chromosome _ the _-____ tyrosine kinase is present and on chromosome __ the ___ gene is present. The genes are split half way through so the C terminal of _-___ (kinase domain) and that fuses on chromosome __ containing the N terminal of the ___ gene. So _-___ the protein tyrosine kinase is folded in resting cells by intramolecular binding so the _____ domain folds over the _____ domain rendering it inactive. If you splice that gene half way through and fuse the kinase domain to the ___ gene, it can’t fold over the kinase domain so the molecule remains open and is ______ active. SO would wouldn’t need to ______ the regulatory domain to unfold the protein so it can engage with the receptor to activate cell growth and proliferation as it is always active. You can’t target this with _______ as it is NOT a receptor. It is an CYTOPLASMIC PROTEIN like SRC. It is recruited to receptor complexes when activated. BUT if it is ______ active then the kinase domain _________ it’s targets all the time. The _-___ drives cellular proliferation and survival. It can also move into the _____ and _____ TFs to drive cell growth and proliferation.
9 elongates 22 shorter 9 c-ABL 22 BCR c-ABL 22 BCR C-ABL Regulatory Kinase BCR Constitutively active Phosphorylate Antibodies Constituatively Phosphorylates c-ABL Nucleus Phosphorylates
To screen for CML a blood sample will be taken to detect for the _____ chromosome (22q). Lots of immature ___ will be seen as the ___-____ has lots of tyrosine kinase activity to drive cell growth and proliferation.
Philadelphia
WBC
BCR-ABL
Many intracellular signalling pathways are constitutively activated due to ___-___ chromosomal translocation.
- It activates and is activated by the ___ pathway
- It interacts with the ____ pathway which leads to activation of ___ and is pro survival
- It links into the JAK STAT signalling pathway which is in WBCs and it is shown that constit active ___-___ leads to upreg of STAT signalling and proliferation. Can try to target ___-___ itself or think about some of these other pathways. BUT these pathways are ubiquitous so as ___-___ is only in cancer cells this is a better target. Assume that ___-___ mutation is one of the early mutation (in chronic phase) and then other mutations are responsible for progression to ____ phase
BCR-ABL RAS PI3K PKB BCR-ABL BCR-ABL BCR-ABL BCR-ABL Acute
