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Myelodysplastic Syndrome Pathogenesis and clinical findings

Myelodysplastic Syndrome (MDS): Pathogenesis and clinical findings Authors: Mao Ding Reviewers: Ashar Memon Man-Chiu Poon Yan Yu* * MD at time of publication Stem cells differentiateà accumulation of bone marrow cells with aberrant morphology & maturation Idiopathic (unknown cause) Treatment related: exposure to ionizing radiation, chemotherapeutic agents (e.g., alkylating agents, anti- metabolite, topoisomerase II inhibitors) Environmental toxins (e.g., tobacco, benzene & other organic solvents) Familial predisposition to MDS Acquired somatic (non- reproductive) gene mutations (DNA alterations) Inherited germline (reproductive cells) gene mutations Recurrent mutations cause alteration(s) in one or more protein functions with/without chromosomal abnormalities in hematopoietic stem cell (earliest cell of blood cell differentiation): Mutation in the transcription factor gene RUNX1 impairs regulation of normal hematopoietic (blood cell) development Mutation(s) in epigenetic regulator genes (DNMT3A, TET2) impairs regulation of DNA methylation Mutation in splicing regulator genes (SF3B1) causes mistakes in splicing mRNA moleculesàaberrant translation (production) of proteins Chromosomal abnormalities: deletions (chromosome 5, 7, and/or 20), duplications (chromosome 8), structural abnormalities (inversion of a gene segment) Myelodysplastic Syndrome Mutation-associated clonal disorders of hematopoietic stem cells, causing dysplasia (abnormal development) of one or more myeloid cell lineages (granulocytes, monocytes, red blood cells & platelets) in the bone marrow Genetic mutations or chromosomal abnormalities occur in hematopoietic stem cellsàclonal expansion of abnormal cells in bone marrow Apoptosis (programed cell death) of clonal cells, inhibiting development of granulocytes, monocytes, red blood cells & platelets in the bone marrow Neoplastic myeloid precursor cells (blasts) accumulate in the bone marrow Acute Myeloid Leukemia (AML) > 20% Blasts in the bone marrow Excessive blasts displace other precursor cells & inhibit differentiation Pancytopenia (↓ number of cells of ALL 3 cell lines: platelets, white blood cells & red blood cells) (see Acute Myeloid Leukemia for signs/symptoms/complications) ↓ Number of mature functional blood cells leave the bone marrow to go to peripheral bloodà↓ number of cells of one or more cell lines Bone marrow’s inability to make sufficient blood cells cause extramedullary hematopoiesis (formation/activation of blood cells outside the medulla of bone) at sites such as liver and/or spleen Hematopoietic stem cells migrate to the spleen/liver & differentiate into blood cells Expanding bone marrow physically pushes on bone’s cortex from within, activating nociceptors Multifactorial causes mostly with unclear mechanisms Intracellular granules precipitate inside blasts & the precipitate spills into the blood ↑Division & death of cancerous cells → ↑ cell lysis & release of intracellular contents into plasma Bone pain B symptoms: Weight loss, fever, night sweats Auer Rods (needle- like crystals) seen on blood smear ↑ Serum levels of uric acid, K+, LDH ↓ Red blood cells Anemia fatigue, pallor ↓ White blood cells Leukopenia Recurrent infections ↓ Platelets Thrombo- cytopenia Bruising, bleeding Accumulation of cells within the spleen/liver increase the size of the organ Splenomegaly Hepatomegaly Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published March 4, 2023 on www.thecalgaryguide.com