64. Targeted therapy - general characteristics. Targeted therapy in chronic myeloid leukemia (CML).
Covers the Philadelphia chromosome and the BCR-ABL fusion gene as the molecular basis of chronic myeloid leukaemia, then the pathogenic cascade from the abnormal tyrosine kinase to leukaemic cell accumulation. It goes on to explain how tyrosine kinase inhibitors work, the imatinib first-generation drug, and the resistance mechanisms that led to second- and third-generation agents. The note also addresses molecular monitoring, response goals, differences across disease phases, and the limitations of lifelong therapy.
Topic 64 of 65 in the MU Sofia syllabus for Genetics (Medicine, Year 3). The free AceMed note covers it in 11 sections, about 400 words (3 min of reading), with 16 flashcards.
In this note
Targeted therapy - general characteristics. Targeted therapy in chronic myeloid leukemia (CML).
I. MOLECULAR BASIS OF CML
II. PATHOGENESIS OF CML
III. TARGETED THERAPY STRATEGY IN CML
IV. TYROSINE KINASE INHIBITORS (TKIs)
V. FIRST-GENERATION TKI
VI. SECOND- AND THIRD-GENERATION TKIs
VII. MONITORING OF TARGETED THERAPY IN CML
VIII. TARGETED THERAPY ACROSS CML PHASES
IX. LIMITATIONS OF TARGETED THERAPY IN CML
X. ROLE OF TARGETED THERAPY IN MODERN HEMATOLOGY
I. MOLECULAR BASIS OF CML
Chronic myeloid leukemia is defined by the presence of the Philadelphia chromosome, resulting from a reciprocal translocation t(9;22).
This translocation creates the BCR-ABL fusion gene, which encodes a constitutively active tyrosine kinase.
Why BCR-ABL Is Central
The BCR-ABL protein:
continuously activates growth and survival pathways,
is independent of normal regulatory control,
drives uncontrolled proliferation of myeloid cells.
Because CML is driven by one dominant molecular abnormality, it is an ideal disease for targeted therapy.
II. PATHOGENESIS OF CML
1. Formation of BCR-ABL fusion gene.
2. Production of abnormal tyrosine kinase.
3. Continuous activation of signaling pathways (RAS/MAPK, PI3K/AKT, JAK/STAT).
4. Increased proliferation of myeloid progenitors.
5. Reduced apoptosis.
6. Accumulation of leukemic cells in bone marrow and blood.
III. TARGETED THERAPY STRATEGY IN CML
Targeted therapy in CML is based on selective inhibition of the BCR-ABL tyrosine kinase, which:
suppresses leukemic cell proliferation,
restores normal hematopoiesis,
spares most normal cells.
This represents a paradigm of precision medicine.
IV. TYROSINE KINASE INHIBITORS (TKIs)
Tyrosine kinase inhibitors:
bind to the ATP-binding site of the BCR-ABL kinase,
prevent phosphorylation of downstream proteins,
block oncogenic signaling.
Effect on Leukemic Cells
1. Inhibition of BCR-ABL activity.
2. Suppression of proliferative signaling.
3. Induction of apoptosis in leukemic cells.
4. Reduction of leukemic clone.
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