Myelodysplastic syndromes in Pakistan

Assumption
Myelodysplastic syndromes (MDS) represent a group of myeloid (bone marrow) stem cell
disorders that gradually affect the ability of a person's bone marrow to produce normal red blood
cells, white blood cells, and platelets. Myelodysplastic syndromes (MDS) are clonal hematopoietic
stem cell disorders characterized by abnormal cellular differentiation and maturation with variable
progression to acute leukemia
People with myelodysplastic syndromes have a risk of the disease progressing to acute myeloid
leukemia (AML), which is a bone marrow malignancy. Some studies suggest that AML is a natural
progression of MDS and not a separate disease. In some people, MDS may gradually progress over
a period of many years while in others it progresses rapidly to AML.

Scientists are making progress in understanding how changes in the DNA (genes) inside normal
bone marrow cells can cause them to develop into myelodysplastic cells. It’s also clear that not all
cases of MDS have the same gene changes. An improved understanding of this is helping to better
classify different types of MDS and to determine a person’s likely prognosis (outlook). It might
also help determine which patients might benefit most from different types of treatment.

Scientists are also learning how bone marrow stromal cells influence MDS cells. Stromal cells in
the bone marrow do not develop into blood cells. Instead, they help support, nourish, and regulate
the blood-forming cells. Some studies suggest that although the stromal cells in MDS patients are
not cancerous, they are not normal either, and seem to have a role in causing MDS.

As more information from this research unfolds, it may be used to help develop new drugs or other
types of treatment.
. Over the last decade, scientific discoveries have unraveled specific pathways involved in the
complex pathophysiology of MDS. Prominent examples include aberrations in cytokines and their
signaling pathways (such as tumor necrosis factor-alpha, interferon-gamma, SMAD proteins),
mutations in genes encoding the RNA splicing machinery (SF3B1, SRSF2, ZRSR2, and U2AF1
genes), mutations in genes disrupting the epigenetic machinery (TET2, DNMT3A, DNMT3B,
EZH2, ASXL1). In addition, abnormalities in regulatory T-cell dynamics and atypical interactions
between the bone marrow microenvironment, stroma and progenitor cells, and abnormal
maintenance of telomeres are also notable contributors to the complex pathogenesis of MDS.
These pathways represent potential targets for novel therapies. Specific therapies include drugs
targeting aberrant DNA methylation and chromatin remodeling, modulating/activating the
immune system to enhance tumor-specific cellular immune responses and reduce anomalous
cytokine signaling, and blocking abnormal interaction between hematopoietic progenitors and
stromal cells.

Hypothesis

Scientists have identified some of the chemical signals that are exchanged between stromal cells
and MDS cells.

Recurrent cytogenetic abnormalities are demonstrated in approximately fifty percent cases of MDS
and are an important tool of establishing clonality and defining prognosis [3]. Among karyotypic
abnormalities, partial or complete deletion of the long arm of chromosome 5 [del(5q)] is the most
frequent cytogenetic abnormality found in MDS patients, occurring in 10-15% of all newly
diagnosed MDS patients and in up to 30% of cases with additional abnormal cytogenetic
abnormality

Theoretical Framework
Materials and Methods

Patients

A cross-sectional analysis was conducted in the Department of Hematology of the Armed Forces
Institute of Pathology, Rawalpindi, from January 2013 to January 2017. All patients were
Pakistanis, of Asian origin, belonging to different ethnic groups including Punjabis, Pashtuns,
Sindhis, Balochis, Kashmiris, and those from Gilgit-Baltistan. Patients were between the ages of
30 and 85 years. These patients were newly diagnosed with MDS and had no previous history of
any treatment. All subjects were thoroughly informed about the study and written informed
consent was obtained.

Clinicohematological Parameters

Detailed history was recorded and complete physical examination was done. Symptoms and signs
were noted. Complete blood count, peripheral blood film, and bone marrow examination were
done and patients were diagnosed as having MDS based on the WHO criteria.

Cytogenetics and FISH

Cytogenetic analysis was performed by using the conventional G banding technique. A bone
marrow specimen of 3 mL was collected in sodium heparin. Metaphase chromosomes were banded
using the conventional Giemsa trypsin banding technique and karyotyped according to the
International System for Human Cytogenetic Nomenclature criteria. At least twenty metaphases
were analyzed with the CytoVision semiautomated image analysis and capture system.

Interphase FISH studies were performed on blood or bone marrow specimens processed by
standard methods for cultured samples. The MetaSystems XL 5q31/5q33 probe (10 µL) was
applied to the target on the slide. A total of 500 nuclei were analyzed per probe set by using a
fluorescent microscope with an orange green spectrum filter