Chronic Myeloid Leukemia Overview

Chronic Myeloid Leukemia (CML)

• BCR-ABL is causally linked to CML, acting as a dominant oncogene.
• CML is fatal without treatment; death is highly probable.

Cell Division and Fate

• Dividing cells can self-replicate, differentiate, or undergo apoptosis.
• Cell death (apoptosis) is necessary to maintain a stable cell population.
• Hematopoietic stem cells (HSCs) divide to create identical daughter cells and cells committed to differentiation.

Mature Blood Cells and Replacement

• Circulating cells (red blood cells, neutrophils) cannot divide; replacements need to originate from precursor cells like HSCs

Hematopoietic Stem Cell Control

• HSCs transition, proliferate, and differentiate, heavily regulated by soluble mediators (e.g., cytokines, growth factors) and microenvironmental factors.
• Dysregulation can cause excessive effector cell proliferation or stem cell overproduction (malignant transformation).

Malignancy in Hematopoietic Cells

• Malignancies commonly arise in HSCs, due to their long lifespan and self-renewal capacity, increasing mutation accumulation risk.
• Mutations perpetuate within the cell population and ultimately cause proliferation of malignant cells

CML as a Stem Cell Malignancy

• CML involves stem cell overactivation, leading to enhanced HSC self-renewal, increased proliferating cell survival, and a rise in mature cells in circulation.
• Chronic phase is characterized by excessive stem, proliferating, and mature cell production, potentially lasting years without treatment.
• Normal HSCs balance proliferation and differentiation. Malignant HSCs disrupt this balance, causing overproduction.

Clinical CML (Chronic Phase)

• The chronic phase is not initially fatal.
• CML cells functionally mature but replace normal bone marrow cells.
• Elevated numbers lead to potential blood vessel blockage (thrombosis risk), organ swelling (spleen/liver), fatigue, and can last 4-6 years untreated.
• Progresses towards more aggressive phases (acceleration, blast crisis).

CML Acceleration and Blast Crisis

• Acceleration phase occurs roughly a year after the chronic phase begins.
• Blast crisis (terminal phase), lasts about 3-6 months.
• Loss of differentiation leads to functionally useless, immature blast cells in the proliferating pool. Mature cell production ceases, leading to an inability to maintain normal cell function.
• Possible outcomes include anemia, infections, and bleeding (due to insufficient red blood cells, mature immune cells, and low platelets).

CML and the Role of Tyrosine Kinases

• Cytoplasmic tyrosine kinases, such as ABL, often involved in human cancers, play crucial roles in signaling pathways.
• Abnormal ABL (p210BCR-ABL) results from a translocation (Philadelphia chromosome Ph1) combining BCR and ABL genes. This initiates uncontrolled kinase activity.

p140c-abl (Normal Protein)

• Normal ABL (p140) participates in normal signaling; it is not oncogenic (non-cancer-causing).
• Has multiple domains (SH3, SH2, PTK, and NLS)
• Primarily cytoplasmic, shuttling to the nucleus when activity is low. Activation through phosphorylation prevents entry into the nucleus.
• Typically a tumor suppressor, promoting apoptosis in cells with DNA damage.

p160gag-abl

• Discovered in a retrovirus that causes Abelson leukemia.
• Contains a viral gag protein and an abl domain. Exhibits strong tyrosine kinase activity, critical for cell transformation
• Implicated in uncontrolled cell growth and leukemia.

p210bcr-abl

• Abnormal protein from BCR-ABL translocation.
• 210 kDa; ABL kinase domain, but BCR amino-terminus
• Characterized by strong, unregulated tyrosine kinase activity.
• Linked to abnormal cell proliferation and resistance to apoptosis.

Philadelphia Chromosome (Ph1)

• Chromosomal translocation in CML.
• BCR and ABL genes fuse.
• Results in p210BCR-ABL fusion protein, with significantly increased tyrosine kinase activity.

Importance of Tyrosine Kinase Activity

• p210BCR-ABL's tyrosine kinase activity constantly activates signaling pathways.
• This promotes cell survival, growth, and proliferation, resulting in CML hallmark features.
• BCR-ABL acts as a dominant oncogene. Its presence on its own can cause cancer characteristics.

Clinical Oncology vs. Molecular Genetics

• Clinical oncology focuses on treating patients in CML (e.g., chemo, transplantation).
• Molecular genetics studies the underlying mutations (BCR-ABL fusion gene) for targeted therapy.
• Aim is to eliminate the cells responsible.

CML Treatment – Bone Marrow Transplantation

• Replaces cancerous bone marrow with healthy donor cells post-treatment.
• Types include: autologous (patient's own) and allogeneic (donor).
• Allogeneic poses risks of GVHD and rejection from donor cells.
• Potential cure, but high risk of failure and death in advanced phases, notably lower success rates in later stages. Bone marrow from donor can attack the recipient host or cause lethal infections.

This quiz covers essential concepts related to Chronic Myeloid Leukemia (CML), including the role of the BCR-ABL oncogene and the importance of hematopoietic stem cells in blood cell formation. Understand the balance between cell division, differentiation, and apoptosis in maintaining a stable cell population, and the potential for malignancy in hematopoietic cells.