Prepared by: Dr.Mansour Al-Yazji

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1 C L L CLL Prepared by: Abd El-Hakeem Abd El-Rahman Abu Naser Ahmed Khamis Abu Warda Ahmed Mohammed Abu Ghaben Bassel Ziad Abu Warda Nedal Mostafa El-Nahhal Dr.Mansour Al-Yazji

2 LEUKEMIA Leukemia is a form of cancer that begins in the blood-forming cells of the bone marrow occurs when there is an excess of abnormal white blood cells in the blood.

3 Types of leukemia There are two classification criteria for leukemia which determines the type of leukemia. It involves the rate of developement and the type of white blood cells that are affected. These classification criteria include: 1. Developmental and progression rate: CHRONIC LEUKEMIA: This is a type of leukemia characterized by a slow progression. In its early stages, chronic leukemia is asymptomatic, because the small number of abnormal white blood cells still can carry out some of the normal white blood cells functions. Symptoms occur in advanced stages when the number of abnormal white blood cells increases. ACUTE LEUKEMIA: This is a type of leukemia characterized by a rapid progression caused by an increased number of abnormal white blood cells. Acute leukemia can be fatal within weeks or months if not treated.

4 2. Type of white blood cells involved, which include: Lymphocytic leukemia: This is a type of leukemia that affects the lymphoid cells. Myeloid leukemia: This is a type of leukemia that affects the myeloid cells.

5 According to the above Chronic/Acute -AND- Lympocyte/Myeloid criteria, there are main types of leukemia: I. Chronic Lymphocytic Leukemia II. Chronic Myelogenous Leukemia III. Acute Lymphocytic Leukemia IV. Acute Myeloid Leukemia

6 Chronic Lymphocytic Leukemia CLL CLL is a neoplastic disease characterized by proliferation and accumulation (blood, marrow and lymphoid organs) of morphologically mature but immunologically dysfunctional lymphocytes.

7 Overview The most common type of leukemia in the westren world Disease of elderly (50-60 years) 2:1 ratio of male to female Rare cases it can occur in teenagers and occasionally in children (inherited) High familial risk with two-fold to seven-fold higher risk. No documented association with environmental factors. The survival rate can vary between 1 to 20 years

8 Risk Factors Age: CLL usually occurs in adults over the age of 50. Gender: CLL is more common among men. Race: CLL is more common among Caucasians. Family history: CLL is more common among adults that have a family history of chronic lymphocytic leukemia or cancer of the lymph system, or have Russian Jews or Eastern Europe Jews relatives. Certain chemical exposures

9 Symptoms Asymptomatic in its early stages. Some of the most common symptoms are: Abnormal bruising (occurs late in the disease) Enlarged lymph nodes, liver, or spleen Excessive sweating, night sweats Fatigue Fever Infections that keep coming back (recur) Loss of appetite or becoming full too quickly (early satiety) Unintentional weight loss

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11 B-CELL ACTIVATION AND MATURATION The enormous diversity of the normal B-cell-antibody repertoire initiates in the bone marrow where B lymphocytes rearrange their immunoglobulin (Ig) variable (V) region gene segments coding for the B cell s receptor for antigen (BCR) When the B cell enters a lymphoid follicle and, with the help of other cells and cytokines, creates a structure called the germinal center (GC) where the cell proliferates and accumulates somatic mutations in its BC Rencoding genes. These mutations may produce amino acid changes in the binding site of the BCR, which can improve or create new antigen-binding specificity.

12 Enhanced affinity B cells survive, whereas those having BCRs that either do not bind antigen or bind self-antigens die. The GC reaction usually occurs in secondary lymphoid follicles with the help of T lymphocytes.

13

14 CHARACTERIZING THE HETEROGENEITY OF B-CLL BY MOLECULAR AND CLINICAL SUBTYPES Most B-CLL cells also express activation markers and, like normal activated B cells, CD19, CD20, CD21, and CD23 monoclonal antibodies. They expression of CD5, which is more typically found on T cells. Because normal CD5 + B cells are present in the mantle zone (MZ) of lymphoid follicles, B-cell chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) is most likely a malignancy of an MZ-based subpopulation of anergic self-reactive cells devoted to the production of polyreactive natural autoantibodies

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16 B-cell chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) cells express extremely low levels of surface membrane immunoglobulin, most often IgM and IgD. Additionally, they also express extremely low levels of a single immunoglobulin light chain (kappa or lambda).

17 Based on their mutation status, B-CLL patients can be divided into two groups: B-CLL cells use unmutated IgVH genes (U-CLL. (virgin cell) B-CLL cells use mutated IgVH genes (M-CLL). (memory cells)

18 B-CLL clones can be further subdivided based on their activation marker expression: CD38 + and ZAP-70 + CD38 - and ZAP-70 Zeta-chain-associated protein kinase 70 (70 is the molecular weight in kda). The protein is a member in the protein-tyrosine kinase family. ZAP-70 is normally expressed in T cells and natural killer cells and has a critical role in the initiation of T-cell signaling

19 Markers CD38+ZAP-70+ B-CLL clone generally use unmutated IgVH genes, whereas CD38 ZAP-70 B-CLL clones mainly use mutated IgVH region genes. about 25 percent of cases are discordant for the expression of the three markers.

20 Express mutated IgVH genes generally fare better and have a good prognosis. In those individual cases that are discordant for the expression of these markers, there is nevertheless generally a direct correlation

21 An abnormal karyotype is The most common abnormality is deletion of 13q, which occurs in more than 50% of patients. Individuals showing 13q14 abnormalities have a relatively benign disease that usually manifests as stable or slowly progressive isolated lymphocytosis. The presence of trisomy 12, which is observed in 15% of patients, is associated with atypical morphology and progressive disease. Deletion in the short arm of chromosome 17 has been associated with rapid progression, short remission, and decreased overall survival in chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL). 17p13 deletions are associated with loss of function of the tumor suppressor gene p53. Deletions of bands 11q22-q23, observed in 19% of patients, are associated with extensive lymph node involvement, aggressive disease, and shorter survival.

22 Causes As in the case of most malignancies, the exact cause of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) is uncertain. The protooncogene bcl2 is known to be overexpressed, which leads to suppression of apoptosis (programmed cell death) in the affected lymphoid cells. In the majority of cases, this appears to be secondary to alterations in the expression of the mirnas MIRN15a and MIRN16-1. Chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) is an acquired disorder, and reports of truly familial cases are exceedingly rare.

23 DEVELOPMENT OF B-CLL FROM NORMAL B LYMPHOCYTES: SIGNALS AND MECHANISMS INITIATING THE GROWTH AND ACCUMULATION OF LEUKEMIC LYMPHOCYTES

24 The major events in tumorigenesis: Inducing factors :(cause transforming mutations) promoting factors: (sustain the proliferation )

25 Although characteristic DNA abnormalities can occur later in the development of B-CLL clones, these are rarely found in the initial phases of the disease. Foreign antigens or auto antigens could prompt normal B lymphocytes to become B-CLL cells by selecting B-cell clones with restricted stereotypic BCRs.

26 How would the transition from normal B cells to leukemic cells via antigen stimulation occur? B-CLL cells frequently display polyreactive BCRs, thereby making it possible that they derive from normal polyreactive B lymphocytes that have been repeatedly stimulated.

27 However, expansion would stop if IgV gene mutations alter BCR structure in such a way that antigen binding is no longer sufficient to induce B-cell signaling.

28 In addition to antigen stimulation, B-CLL cells also receive receptor-mediated signals as well as soluble factors, such as cytokines and chemokines up-regulate anti-apoptotic genes, such as Bcl-2, survivin, and Mcl-1, which could rescue B-CLL cells from apoptosis and facilitate their growth.

29 Morphology In CLL, sheet small round lymphocytes and scattered efface involved lymph nodes. The foci mitotically active cells are called proliferation centers. The neoplastic cells are fragile and are frequently disrupted during the preperation the smears (smudge cells)

30 Correlations between the cellular and molecular features of the disease with the clinical course of B-CLL The disease manifests differently in different patients depending on : Mutated or unmutated IgVhH genes Expression of ZAP-70 and CD38 by leukemic cells In vivo : more activation markers are found on U-CLL so they have self-reacting BCR while M-CLL don t. continuous stimulation represents a major factor for U-CLL and less for M-CLL

31 Relation between chromosomal abnormalities and clinical course of patient chromosomal abnormalities in B-CLL include: Deletion at : 13q q p13 6q21 Amplification of all or portions of chromosome 12 It is more frequently found in U-CLL

32 Deletion at 13q14.3 is most common in B-CLL cases It is linked to loss of two micro-rnas that regulate Bcl-2 expression It is not dangerous because deletion is on one allele Deletion of other genes is associated with more aggressive because it may affect important genes such as p53

33 Clinical Features Onset after age 50 Male predominance male-female ratio 2:1 Nonspecific symptoms weight loss, anorexia and easy fatigability Generalized lymphadenopathy and hepatosplenomegaly Lymphocytosis Immune abnormalities hypogammaglobulinemia autoantibodies against erythrocytes or platelets

34 THERAPY The generally used practice is to wait to start therapy until the patient s clinical course becomes evident ( wait and watch mode). New knowledge about the biology of B-CLL can provide clues for novel therapeutic targets. For example, since B-CLL cells must interact with the stroma in bone marrow or other peripheral lymphoid tissues to survive, furthering our knowledge of these interactions may generate new objectives for innovative therapies. Another compelling set of options may derive from specific inhibition of the BCR or CD38 signaling pathways or other pathways in which ZAP-70 is crucial.

35 THANKs For All Of U Abd El-Hakeem Abd El-Rahman Abu Naser Ahmed Khamis Abu Warda Ahmed Mohammed Abu Ghaben Bassel Ziad Abu Warda Nedal Mostafa El-Nahhal

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