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

C LL CLL

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.

Types of leukemiaThere 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.

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.

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

Chronic Lymphocytic Leukemia “CLL”

CLL is a CLL is a neoplasticneoplastic disease disease characterized by proliferation characterized by proliferation andand accumulation accumulation ((blood, marrow and lymphoid blood, marrow and lymphoid organsorgans)) of of morphologically mature but immunologically dysfunctional morphologically mature but immunologically dysfunctional llymphocytesymphocytes..

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

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

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

B-CELL ACTIVATION ANDMATURATION

• 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.

• 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.

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

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).

Based on their mutation status, B-CLLpatients 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)

• 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

• 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.

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

•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.

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.

DEVELOPMENT OF B-CLL FROM NORMAL B LYMPHOCYTES:

SIGNALSAND MECHANISMS INITIATING

THE GROWTH AND ACCUMULATION OF

LEUKEMIC LYMPHOCYTES

•The major events in tumorigenesis:

•Inducing factors :(cause transforming mutations)

•promoting factors: (sustain the proliferation )

• Although characteristic DNA abnormalities can occur later in

the development of B-CLL clones, these are rarely found rarely found in in

the the initial phases of the diseaseinitial 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.

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.

• 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.

•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.

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)

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

Relation between chromosomal abnormalities and clinical course of patient

chromosomal abnormalities in B-CLL include:

� Deletion at :

• 13q14.3

• 11q22-23

• 17p13

• 6q21

�Amplification of all or portions of chromosome 12

It is more frequently found in U-CLL

�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

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”

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.

Abd El-Hakeem Abd El-Rahman Abu NaserAhmed Khamis Abu Warda

Ahmed Mohammed Abu GhabenBassel Ziad Abu Warda

Nedal Mostafa El-Nahhal

THANKs For All Of U