Apart from the RARa and APL gene translocations, are there other types of translocations?
RARa and APL translocation accounts for 95% of all cases.
However, there are 8 other less common translocations. They always involve RARa
(If they ask us to name all the translocations then that’s slack af because it’s too hard to remember)
What are the names of proteins that the oncogenic PML/RARA protein recruits?
- Nuclear co-repressor (NCOR) molecule:
* Histone deacetylase (HDAC):
What are the functions of the two proteins that the PML/RARA protein recruits?
Nuclear co-repressor (NCOR) molecule:
* This recruits HDAC
Histone deacetylase (HDAC):
- This an enzyme
- Under normal circumstances, histones are wrapped around DNA in chromosomes to provide structural integrity
- To carry out gene expression, a cell must control the coiling and uncoiling of DNA around histones
- This is accomplished with the assistance of histone acetyl transferases (HAT), which loosens the bond of the histones around the DNA, exposing so it can be more easily transcripted
- Conversely, Histone deacetylases (HDAC) leads to the formation of a more tight wrap of histones around DNA, covering it. Thus, the DNA is blocked from being transcripted
What is the prognosis for APL?
If it is diagnosed and treated early, it is very good. Relapses are very good.
However, if left undiagnosed and untreated, prognosis is poor (median survival of less than a month. The most common cause of death is severe bleeding.
How does APL cause excessive bleeding?
The coagulopathy associated with APL is multifactorial:
- Not enough platelets due to bone marrow crowding
- Molecules such as Annexin II is present on the surface of APL cells. This activates plasmin, a molecule that breaks down blood clots
- Molecules such as Tissue factor 9 (TF) causes clotting factors to be made = lots of blood clots
There are a lot of blood clots being made, then you have destruction of those blood clots by Annexin II = lots of bleeding
In APL, are there a high amount of white blood cells?
Yes, because that is what is affected.
Promyelocytes would have eventually gone on to form white blood cells. Instead, they become stuck at this stage and excessively proliferate.
Eventually, the number of white blood cells will decrease as the bone marrow becomes crowded.
Explain how “fluorescence in situ hybridization (FISH)” would be used to diagnose PML
- The first step is to prepare a single-stranded DNA that match a portion of the gene the researcher is looking for. These are called probes
- These probes have fluorescent dyes attached to them
- DNA is composed of two strands of complementary molecules that bind to each other like chemical magnets. Since the researchers’ probes are single-stranded, they are able to bind to the complementary strand of DNA, wherever it may reside on a person’s chromosomes
- When a probe binds to a chromosome, its fluorescent tag provides a way for researchers to see its location
Explain how “polymerase chain reaction” (PCR) would be used to diagnose PML. Why would such a process be used?
- Its goal is to amplify a segment of DNA
- The sample taken from the patient is heated so the DNA separates into two pieces of single-stranded DNA
- An enzyme called “Taq polymerase” synthesizes two new strands of DNA, using the original strands as templates
- This process results in the duplication of the original DNA, with each of the new molecules containing one old and one new strand of DNA
- Each of these strands can be used to create two new copies, and so on, and so on
Why is this process used?
Because significant amounts of a sample of DNA are necessary for molecular and genetic analyses, studies of isolated pieces of DNA are nearly impossible without PCR amplification.
What is APL differentiation syndrome?
Differentiation syndrome (DS) is a life-threatening complication in patients with acute promyelocytic leukemia (APL) undergoing induction therapy with all-trans retinoic acid (ATRA) or arsenic trioxide (ATO).
Symptoms/ conditions like the following are experienced:
- Fluid retention
- Labored breathing
- Fluid accumulation around the heart or lungs
- Episodes of hypotension
What is a side effect of ATO?
Name: QT Interval Prolongation
It affects electrolyte levels (essential minerals in the
blood such as potassium, magnesium, and calcium), which can cause a heart rhythm disorder known as “QT interval prolongation.”
This disorder causes fast heartbeats that may
lead to sudden fainting or seizures.
At what times is ATRA and ATO used?
ATRA is used to mature the promyelocytes into granulocytes.
ATO helps with destroy any leukemic cells.
ATO is used alongside with ATRA, and, it i the recommended therapy for patients who do not achieve remission at the end of the consolidation phase.
What is vitamin A and how are retinoids and retinoic acids related to it?
Vitamin A is a group of nutritional organic compounds that includes retinol, retinal, retinoic acid, and several provitamin A carotenoids.
What is HLA?
- HLA stands for human leukocyte antigens.
- They are proteins on most cells in the body
- All of us inherit many different HLA genes from our parents
- The immune system uses HLA to recognize which cells belong to the body and which do not
- Almost all cells with a nucleus have class I HLA molecules
- There are 6 HLA types that are important for stem cell transplants: in a bone marrow transplant the patient and donor must match at all 6 (100% match)
If ATRA works the same way a retinoid would, why can’t normal retinoids help cure APL through cell differentiation?
PML-RARa protein and its recruits are normally not sensitive to retinoic acids, however the protein seems to be very sensitive to ATRA.
The reason for this is unclear, but this conclusion was deduced from the fact that in patients who had a mutation to the PML-RARa protein, ATRA resistance occurred.
