Identification and In Silico

Analysis of MUC19 Gene

Variants
in Chronic Myeloid
Leukemia Patients(CML)

Presenter:
NIMRA
MBFS20-F22
Supervisor:
Dr. Muhammad Farooq Sabar
Co-Supervisor:
Dr. Usman Ghani
DNA Core Facility
 INTRODUCTION

Chronic myeloid leukemia

is characterized by an
excessive and unregulated
production of white blood
cells by the bone marrow.

The development of
chronic myeloid leukemia
is linked to a specific
genetic abnormality, the
Philadelphia chromosome.

https://www.cancercouncil.com.au/chronic-myeloid-leukaemia/diagnosis/
 INCIDENCE OF CML

About 1 to 2 cases per 100,000 population globally

About 0.34 per 100,000 population in Pakistan

15-20% of all leukemias

Predominantly older adults (male)

https://www.iarc.who.int/wp-content/uploads/2022/06/pr315_E.pdf
 SYMPTOMS

• Feeling fullness after eating only a small amount

• Enlarged spleen
• Frequent and persistent infections

• Tiredness
• High temperature (fever)
• Night sweats

• Bruising or bleeding
• Unexplained weight loss.
• Swollen lymph nodes in the neck, underarms or groin
 Phases of chronic myeloid leukemia

Chronic Phase Accelerated phase Blast phase

• • Initial
C phase • Progressive stage • Third stage

• Patient with mild symptoms • Characterized by an increase in • severe and potentially life-
the number of immature blood threatening phase
• patients may be asymptomatic cells.
• Blast cells are more than 20%.
• Blast cells are less than 10% • Blast cells are 10-20%
• Symptoms: • Symptoms:
• Symptoms:
• Infections, night sweating • Abdominal pain, shortness of
• Weight loss, high fever
• High fever breath, weight loss,
• Feeling of fullness splenomegaly and
• tiredness
• Enlarged spleen hepatomegaly and many other.
• Bone pain and other cml
symptoms.
ALPINE SKI HOUSE
Szuber, N., Elliott, M., & Tefferi, A. (2022). Chronic neutrophilic leukemia: 2022 update on diagnosis, genomic landscape, prognosis, and management. American journal of hematology, 97(4), 491-505.
 DIAGNOSIS

Physical examination Bone marrow biopsy Genetic tests

Blood tests . FISH
.Q-PCR

García-Gutiérrez, V., Breccia, M., Jabbour, E., Mauro, M., & Cortes, J. E. (2022). A clinician perspective on the
treatment of chronic myeloid leukemia in the chronic phase. Journal of Hematology & Oncology, 15(1), 90.
Treatment

Imatinib (Gleevec)
Nilotinib (Tasigna)
Dasatinib (Sprycel)
Bosutinib (Bosulif)
Ponatinib (Iclusig)
Asciminib (Scemblix)
A Leitner, A., Hochhaus, A., & C Muller, M. (2011). Current treatment concepts of
CML. Current Cancer Drug Targets, 11(1), 31-43.
Problem Statement

The Harmonizome database reveals a notable

mutation in the MUC19 gene within CML-T1
cell lines, suggesting a potential role in the
disease pathogenesis. However, the functional
implications of this mutation remain elusive,
posing a critical gap in our knowledge.
Addressing this gap is essential for uncovering
novel therapeutic targets and advancing
precision medicine for CML patients.
 Rationale

• Our preliminary NGS analysis reveals a striking 60bp insertion mutation in MUC19 at
position 40,884,241 in multiple CML patient of accelerated phase, suggesting a potential link
to MUC19 gene with disease progression.
• The 60bp insertion falls within a crucial domain of the Mucin19 oligomeric
protein, potentially impacting its function.
• MUC19 acts as a tissue guardian, anchoring cells, regulating signaling, and shielding them
with sugars, but its dysfunction can unleash uncontrolled growth and invasion .
• MUC19's oncological waltz differs colorectal mutations fuel invasion's fire, pancreatic silence
empowers progression's grip, while breast cells sway between its up-down rhythm and altered
glycosylation's twist, each a tantalizing clue for therapeutic intervention.
• MUC19 gene is relatively unexplored regarding role in CML cancer, presenting an
opportunity for significant discoveries regarding CML diagnosis and prognosis.
Zhu M, Chen E, Yu S, Xu C, Yu Y, Cao X, Li W, Zhang P, Wang Y, Lian B, Zhang S, Qu Y, Huang L, Shi W, Cui Y, Qian L, Liu T. Genomic profiling
and the impact of MUC19 mutation in hepatoid adenocarcinoma of the stomach. Cancer Commun (Lond). 2022 Oct;42(10):1032-1035. doi:
10.1002/cac2.12336. Epub 2022 Jul 19. PMID: 35851588; PMCID: PMC9558685.
Mucin Gene 19 (MUC19) Oligomeric

Chromosome Exons Length

Chr12:40,
787,197- 84 19628bp
40964562
 Mucin Gene 19 Oligomeric

• Mucin family members are glycoproteins that have tandem repeats which
are extensively O-glycosylated. Tumors associated epitopes are generated in
the oligosaccharide side chains of mucins due to changes in their
glycosylation patterns. To detect cancer at the earliest stage, mucins are
analyzed as potential markers of disease progression and diagnosis. It plays
role in different types of cancers
• Breast Cancer
• Colorectal Cancer
• Pancreatic Cancer

Rachagani S, Torres MP, Moniaux N, Batra SK. Current status of mucins in the diagnosis and therapy of cancer. Biofactors. 2009 Nov-Dec;35(6):509-27. doi: 10.1002/biof.64. Erratum in:
Biofactors. 2012 Nov-Dec;38(6):478. PMID: 19904814; PMCID: PMC2846533.
 Objectives of the Study

Evaluation of Association between identified Gene

Variants and Susceptibility to CML in a Case-
Control Study

To analyze the structure and function of the mutated

proteins through in-silico analysis

Bioinformatics tools-based prediction of new

therapeutic drugs for CML disease
 Methodology

Blood Sample and

DNA Extraction Primer Designing
Data Collection

PCR Amplification
of targeted region
of MUC19 gene

DNA Sequence
In-Silico and analysis and
DNA Sequencing
Statistical Analysis variants
identification
Bioinformatics tools-based Drugs Identification

Preparation of
Target selection Ligands selection
Target and ligand

Virtual Screening

ADMET
Toxicity Prediction Md simulations
Assessment

Sohraby, F., Bagheri, M., Aliyar, M., & Aryapour, H. (2017). In silico drug repurposing of
FDA-approved drugs to predict new inhibitors for drug resistant T315I mutant and wild-type
BCR-ABL1: a virtual screening and molecular dynamics study. Journal of Molecular
Graphics and Modelling, 74, 234-240.
 Predicted Outcomes

We will be able to detect and find the MUC19 gene

variants in CML

Will be able to predict the deleterious/pathogenic

effect of identified gene variants on MUC19 protein

New Drugs will be suggested for medicinal

purposes
 • Rowley, J. D. (1973). A new consistent chromosomal
abnormality in chronic myelogenous leukaemia identified
by quinacrine fluorescence and Giemsa
staining. Nature, 243(5405), 290-293.
• Iqbal, Z., Absar, M., Akhtar, T., Aleem, A., Jameel, A.,
Basit, S., ... & Mahmood, A. (2021). Integrated Genomic
Analysis Identifies ANKRD36 Gene as a Novel and
Common Biomarker of Disease Progression in Chronic
Myeloid Leukemia. Biology, 10(11), 1182.
• Cortes, J. E., Saglio, G., Kantarjian, H. M., Baccarani, M.,
Mayer, J., Boqué, C., ... & Hochhaus, A. (2016). Final 5-

References
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