UNIVERSITY OF ROCHESTER PERSONALIZED MEDICINE FINAL

CHILDHOOD LEUKEMIA RESEARCH AND DISCOVERY

Abigail Moreno
AGENDA

→ OMIM Data
→ Academic Paper Key Points
→ Patient File
→ Patient Sequential Analysis
→ Thought Questions

→ Proposed Treatment
→ Ethical Implications

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OMIM DATA COLLECTED
 Acute lymphoblastic leukemia is a subtype of acute leukemia and a cancer of the white blood cells.
 Somatically acquired mutations in several genes have been identified in ALL lymphoblasts and cells in the early stages of
differentiation

Agermline variation in certain genes may also predispose to susceptibility to ALL
 A susceptibility locus for acute lymphoblastic leukemia (ALL1) has been mapped to chromosome 10q21
 The gene type of ALL is unknown

 The ETV6/RUNX1 fusion gene, found in 25% of childhood a LL cases, is acquired in utero but requires additional somatic mutations for
overt leukemia
 Using Genomic and next generation DNA sequencing technologies, researchers and investigators have revealed that 14% of
children with high risk ALLhave the Philadelphia chromosome(Ph-like)

There has also been more research stating that 40 distinct gene arrangements and fusions can result in the Ph-like ALL.
 Cell lines and human leukemic cells that express some of the different gene fusions are also said to be sensitive to
current available drugs for treatment

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 ❖ The paper discusses 3GWAS that identified
susceptibility loci for B-cell childhood acute
RESEARCH PAPER KEY POINTS lymphoblastic leukemia (BCP-ALL)

Acute lymphoblastic Discussion

leukemia
 Most common pediatric cancer in
western countries
 provides evidence for the existence of
Etiology of ALL is not well understood
 Statistical modeling of GWAS data
shows that much of the heritable risk of
ALL credited to genetic variation remains
undiscovered .
 ALL is biologically heterogenous
 The paper is focused on the meta-
analysis of 2 studies of European
ancestry to gain a more comprehensive
insight to the predisposition to ALL
power to detect alleles conferring more
Results
 Identified three risklociforBCP-ALL
 The analysis across all risk loci combined
revealed that risk SNPS are enriched for
markers of open chromatin and that
enrichment is highest in ALL cells
 Another analysis revealed a significant
enrichment of SNPs within enhancers in
primary hematopoietic stem cells.
 
In the aspect of heritable risk, the 11
known susceptibility variants account for
34% of the familial risk.
 
The impact of BCP-ALL SNPs are among
the strongest GWAS associations of any
malignancy , raising the possibility of clinical
utility for risk prediction.

The entire analysis in this research,
two additional risk loci for childhood
BCP-ALL: 2Q2 2.3 AND 8Q2 4.21

Deregulation of YMC has been reported in
ALL, and in some instances, is a
consequence of chromosomal
rearrangement.
The analysis conducted sheds further light
on inherited predisposition to childhood
ALL
Researchers understand that they had low
moderate effects
 many risk SNPS may yet be
unidentified.
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 PATIENT FILE:
PEDIGREE:
• Orange:pediatricALL
• Green: ovarian cancer
• Yellow: ALL in adulthood
• Red:Prostatecancer

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SEQUENTIAL ANALYSIS TABLE

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 THOUGHT QUESTIONS
1. Is R's ALL hereditary? If so, what are the possible genetic causes of Acute Lymphoblastic Leukemia (ALL)?
 Many types of leukemia are caused by the mutations in the DNA of white blood cells. R’s ALL is hereditary. She possesses the

gene associated with ALL (possessing the risk allele is not necessarily causative of ALL). She inherited genetic features which

increased her chances of getting ALL. Her family’s history of various cancers associated with the variant is a possible genetic

causethedevelopment of ALL is patient R.

2. What is the likelihood that R's parents will have more children with ALL?
 R’s parents arebothunaffectedbythedisease but still carry the mutation because their genotype is both Aa. When making a
Punnet square to uncover the likelihood of the disease being passed on to offspring one can make the inference that there is only
a 25% chance that any of R’s parent’s offspring will have a child affected by ALL. There is a 50% chance for their offspring to
carry the mutation and a 25% chance that they are completely unaffected.

3. Are R's parents' carriers for the disease or was R'sALL caused by a spontaneous mutation? (Being homozygous for
the variant increases chances of developing ALL)
 R’s parents are carriers for the disease. Because her parents' genotype is heterozygous (Aa), they partially carry the trait forthe
recessive disease. Patient R happened to inherit genetic features from her parents that increased her risk and actually caused her
to develop the condition.

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TREATMENT PLAN
 There is no way to prevent childhood cancer such as leukemia because there are no known risk factors. (while in
adults, there can be lifestyle changes)

The exact cause of childhood leukemia is not known
• For my patient, I would recommend
three treatment processes CAR-T Cell Therapy
•1.Chemotherapy This form of therapy is a great asset to
•2. Car-T Cell Therapy treatment in young patients with ALL
• 3. Stem Cell transplant Immune cells called T cells are taken from the
patient's blood, and the cells are genetically
modified to express a protein which will recognize
Chemotherapy: and bind to a target called CD19,
Chemotherapy would be the first step in the found on cancerous ALL cells, targeting them
treatment. directly and leaving the patient cancer free.

Chemotherapy wouldkilloff the cells using drugs

such as L-asparaginase and thiopurines.
Thiopurines (affects the synthesis of A and
G nucleotides preventing the function of
DNA and RNA within cancer cells)
▪I would also recommend getting a round of
chemotherapy outside the area where the cancer
cells were found to make sure it is not found
anywhere else or spread.
Chemotherapy in the Cerebrospinal fluid
would kill cells in the brain and spinal cord.
Reason for Stem Cell Transplant
•The chemotherapy would kill the cancer
cells but unfortunately also healthy cells.
•To reduce the impact that has been
made, a stem cell transplant would be
recommended in severe cases to
replenish and restore the immune
system
•Chemotherapy can cause neutropenia
meaning that body may not be able to fight off
infections
Stem Cell Transplant
•If found to be necessary after the
chemotherapy and CAR-T cell
therapy, a stem cell transplant could
be offered to restore the body’s
blood cells.
•The patient would receive the stem
cells through a catheter placed into
a blood vessel in the chest.
ETHICAL CONSIDERATIONS
 General Ethical questions surrounding gene therapy:
 Who decides which traits are normal and which are considered disabilities
 How the high cost of gene therapies would affect certain populations
 How to differentiate from proper and improper use of gene therapies
 How the widespread use of gene therapies will affect our population
 Should gene therapies be used for things other than treatments such as basic human traits consisting of height, ability, and intelligence?
 Stem CellResearch/ Transplant
 Obtaining stem cells from embryonic stem cells from fertilized eggs goes against many ethical ideas.
 Many believe that the destruction of embryos is against the policy and right to life.
 There are many arguments over how to source embryos: some believe in sourcing them from embryos left over from treatments of fertility diseases,
others think to source them from cloned embryos, while some argue that stem cells should only be taken from human adults.
 Can embryonic stem cell research potentially lead to human cloning? (potential regulations?)
 CAR-TCellTherapy

 Many ethical considerations that are focused upon regarding CAR-T Cell Therapy are focused on the unlimited differentiation potential of iPSC’s (
induced pluripotent stem cells)
 They have the potential to be used in human cloning and are a risk for the next generations on human embryos
 Theideathat clinical research should be designed to minimize harms and maximize benefits is a great ethical implication of new gene therapies
Thank You-
Abigail Moreno
abigail14moreno@gmail.com

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