Chronic Myeloid Leukemia Overview
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Questions and Answers

What primarily causes Chronic Myeloid Leukemia (CML)?

  • Loss of cytokine production
  • Excessive apoptosis in cells
  • Increased differentiation of hematopoietic cells
  • Bcr-abl oncogene (correct)

    • Everyone with CML is likely to survive without treatment.

    False

    What are the three directions that dividing cells can take?

    Self-replication, differentiation, apoptosis

    Hematopoietic stem cells (HSCs) must produce one identical daughter cell and the other daughter cell enters a phase of __________.

    <p>proliferation</p> Signup and view all the answers

    Match the following terms related to hematopoietic cells with their descriptions:

    <p>Hematopoietic Stem Cells = Self-renewing cells that give rise to blood cells Differentiated Cells = Final functional forms that cannot divide Cytokines = Soluble mediators that influence cell behavior Malignancy = Abnormal cell proliferation leading to cancer</p> Signup and view all the answers

    What is a primary consequence of losing control over hematopoietic stem cells?

    <p>Excessive proliferation of effector cells</p> Signup and view all the answers

    Hematopoietic stem cells (HSCs) usually get eliminated early in life.

    <p>False</p> Signup and view all the answers

    What effect does overactivation of hematopoietic stem cells have?

    <p>Increased self-renewal of HSCs</p> Signup and view all the answers

    What causes the Philadelphia chromosome in chronic myeloid leukemia (CML)?

    <p>A reciprocal translocation between chromosomes 9 and 22</p> Signup and view all the answers

    Constitutively active ABL kinase in BCR-ABL fusion proteins enters the nucleus to promote cell proliferation.

    <p>False</p> Signup and view all the answers

    What type of therapy is Imatinib, and what does it target?

    <p>Targeted therapy that blocks the BCR-ABL fusion pathway.</p> Signup and view all the answers

    The two types of bone marrow transplants are __________ and __________.

    <p>autologous, allogeneic</p> Signup and view all the answers

    What percentage of CML patients exhibit the Philadelphia chromosome at diagnosis?

    <p>95%</p> Signup and view all the answers

    Bone marrow transplant during the accelerated phase has the same survival rate as during the first chronic stage.

    <p>False</p> Signup and view all the answers

    What is the role of the BCR-ABL fusion gene in CML?

    <p>It causes abnormal cell growth and survival.</p> Signup and view all the answers

    The presence of BCR-ABL is enough to enable the cell to fulfill the hallmarks of __________.

    <p>cancer</p> Signup and view all the answers

    Match the following BCR-ABL fusion protein types with their characteristics:

    <p>P210 BCR-ABL = Involves BCR exons 1, 2, and 3; longer variant P185 BCR-ABL = Shorter variant of the fusion protein</p> Signup and view all the answers

    What is a major risk associated with allogeneic bone marrow transplants?

    <p>Graft Versus Host Disease (GVHD)</p> Signup and view all the answers

    What characterizes the chronic phase of Chronic Myeloid Leukemia (CML)?

    <p>Excessive production of stem and mature cells</p> Signup and view all the answers

    The chronic phase of CML is typically fatal without treatment.

    <p>False</p> Signup and view all the answers

    What gene is primarily involved in Chronic Myeloid Leukemia (CML)?

    <p>ABL tyrosine kinase</p> Signup and view all the answers

    Chronic Myeloid Leukemia is characterized by a translocation between chromosomes ____ and ____.

    <p>9, 22</p> Signup and view all the answers

    Match the following phases of CML with their characteristics:

    <p>Chronic Phase = Excessive production of normal cells Acceleration Phase = Progression from chronic to acute-like symptoms Blast Crisis Phase = Accumulation of immature, non-functional cells</p> Signup and view all the answers

    What risk is associated with high numbers of functionally normal mature cells in CML?

    <p>Thrombosis</p> Signup and view all the answers

    The presence of normal hematopoietic stem cells (HSCs) ensures a balance of cell types.

    <p>True</p> Signup and view all the answers

    What happens to the cell differentiation abilities in the blast crisis phase of CML?

    <p>Cells lose their ability to differentiate.</p> Signup and view all the answers

    The p210BCR-ABL fusion gene is characterized by strong ___ activity.

    <p>tyrosine kinase</p> Signup and view all the answers

    Match the following proteins with their functions:

    <p>p140c-ABL = Tumor suppressor that promotes apoptosis p210BCR-ABL = Uncontrolled cell proliferation P160gag-abl = Viral oncogenic kinase</p> Signup and view all the answers

    Which of the following is a consequence of the blast crisis phase?

    <p>Anemia</p> Signup and view all the answers

    The Philadelphia chromosome results from a duplication on chromosome 22.

    <p>False</p> Signup and view all the answers

    What is a potential outcome of untreated CML progression?

    <p>Death due to complications from the blast crisis phase.</p> Signup and view all the answers

    In addition to anemia, infections can occur due to a lack of ___ cells during CML blast crisis.

    <p>mature immune</p> Signup and view all the answers

    Match the following features with the corresponding phase of CML:

    <p>Chronic Phase = Relatively stable but severe symptoms may emerge Blast Crisis Phase = Similar to acute leukemia Acceleration Phase = Transition period with fewer symptoms</p> Signup and view all the answers

    Study Notes

    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.

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    Description

    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.

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