Lecture-11-Benign qualitative white blood cell disorders; benign qualitative WBC disorders; acute and chronic leukemias; neoplastic myeloid disorders; lymphoid leukemias..pptx

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1. Benign qualitative white blood cell disorders; benign qualitative WBC disorders; acute and chronic leukemias; neoplastic myeloid disorders; lymphoid leukemias. Prepared by Dr Irakli Glonti [email protected] 2024

2. NON NEOPLASTIC  DISORDERS OF  WHITE CELLS ‹#›

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14. ‹#› Leukemia A group of malignant disorders affecting the blood and blood-forming tissues of Bone marrow Lymph system Spleen Occurs in all age groups

15. ‹#› Leukemia Results in an accumulation of dysfunctional cells because of a loss of regulation in cell division Fatal if untreated Progressive Often thought of as a childhood disease The number of adults affected with leukemia is 10 times that of children

16. ‹#› Leukemia Etiology and Pathophysiology Associated with the development of leukemia Chemical agents Chemotherapeutic agents Viruses Radiation Immunologic deficiencies

17. Classification of leukemias Two major types (4 subtypes) of leukemias Acute leukemias Acute lymphoblastic leukemia (ALL) Acute myelogenous leukemia (AML) (also "myeloid" or "nonlymphocytic") Chronic leukemias Chronic lymphocytic leukemia (CLL) Chronic myeloid leukemia (CML) (Within these main categories, there are typically several subcategories)

18. ‹#› Leukemia Classification Acute versus chronic Cell maturity Acute: clonal proliferation of immature hematopoietic cells (the formation of blood or blood cells ) Chronic: mature forms of WBC; onset is more gradual Nature of disease onset

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21. Many chromosomal aberrations seen in ALL dysregulate the expression and function of transcription factors that are required for the normal differentiation of B and T cell progenitors. Up to 70% of T-ALLs have gain-offunction mutations in NOTCH1, a gene that is essential for T cell differentiation, whereas a high fraction of B-ALLs has loss-of-function mutations in genes that are required for B cell differentiation, such as PAX5. positive for terminal deoxynucleotidyl transferase (TdT) and CD3 ‹#›

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24. ‹#› One mechanism of BCL2 overexpression appears to be chromosomal deletions that lead to the loss of genes encoding micro-RNAs that are negative regulators of BCL2. Also of critical importance are signals generated by surface immunoglobulin (the so-called B cell receptor, or BCR). Approximately 50% of tumors have karyotypic abnormalities, the most common of which are trisomy 12 and deletions involving portions of chromosomes 11, 13, and 17.

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28. ‹#› Greater than 85% of follicular lymphomas have a characteristic (14;18) translocation that fuses the BCL2 gene on chromosome 18 to the IgH locus on chromosome 14. This chromosomal rearrangement results in the inappropriate “overexpression” of BCL2 protein, which you will recall is an inhibitor of apoptosis that contributes to cell survival (Chapters 1 and 6).

29. ‹#› Almost all tumors have an (11;14) translocation that fuses the cyclin D1 gene to the IgH locus. This translocation leads to overexpression of cyclin D1, which you will recall stimulates growth by promoting the progression of cells from the G1 phase to the S phase of the cell cycle

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37. ‹#› Virtually all cases of lymphoplasmacytic lymphoma are associated with acquired mutations in MYD88

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39. ‹#› Acute Myelogenous Leukemia (AML) Leukemia characterized by proliferation of myeloid tissue (as of the bone marrow and spleen) and an abnormal increase in the number of granulocytes, myelocytes, and myeloblasts in the circulating blood One fourth of all leukemias 85% of the acute leukemias in adults Abrupt, dramatic onset Serious infections, abnormal bleeding Uncontrolled proliferation of myeloblasts Hyperplasia of bone marrow and spleen

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43. ‹#› Chronic Myelogenous Leukemia (CML) Excessive development of mature neoplastic granulocytes in the bone marrow Move into the peripheral blood in massive numbers Ultimately infiltrate the liver and spleen

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46. ‹#› Chronic Lymphocytic Leukemia (CLL) Production and accumulation of functionally inactive but long-lived, mature-appearing lymphocytes B cell involvement Lymph node enlargement is noticeable throughout the body ↑ incidence of infection

47. ‹#› Chronic Lymphocytic Leukemia Complications from early-stage CLL is rare May develop as the disease advances Pain, paralysis from enlarged lymph nodes causing pressure

48. ‹#› Hairy Cell Leukemia 2% of all adult leukemias Usually in males > 40 years old Chronic disease of lymphoproliferation B lymphocytes that infiltrate the bone marrow and liver

49. ‹#› Hairy Cell Leukemia Cells have a “hairy” appearance Symptoms from Splenomegaly, pancytopenia, infection, vasculitis Treatment alpha-interferon, pentostatin, cladribine

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52. Polycythemia vera is strongly associated with activating point mutations in the tyrosine kinase JAK2. JAK2 normally acts in the signaling pathways downstream of the erythropoietin receptor and other growth factor receptors. The most common JAK2 mutation, sharply lowers the dependence of hematopoietic cells on growth factors for growth and survival. ‹#›

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