Leukemia

History

• Means “white blood” in Greek

• Discovered by Dr. Alfred Velpeau in France, 1827

• Named by pathologist Rudolf Virchow in Germany, 1845

• Is a malignant hematologic disorder characterized by proliferation of abnormal white cells that infiltrate the bone marrow, peripheral blood and organs.

Leukemia

• Acute Leukemias– Blast (precursor) cells– Rapidly fatal if not treated

• Chronic Leukemias– More mature cells– Longer life expectancy

Classification of leukemias

Acute Chronic

Myeloid origin

Lymphoid origin

Acute Myeloid Leukemia (AML)

Acute Lymphoblastic Leukemia (ALL)

Chronic Myeloid Leukemia (CML)

Chronic Lymphocytic Leukemia (CLL)

Hematopoieticstem cell

Neutrophils

Eosinophils

Basophils

Monocytes

Platelets

Red cells

Myeloidprogenitor

Lymphoidprogenitor

B-lymphocytesB-lymphocytes

T-lymphocytes

Plasmacells

naïve

ALLALL

AMLAML

Myeloid maturation

myeloblast promyelocyte myelocyte metamyelocyte band neutrophil

MATURATIONMATURATION

Adapted and modified from U Va website

Pictures Of Blood

Normal human blood

White Cell Red Cell

Platelet

Blood with leukemia

BlastsRed Cell

Platelet

White Cell

Sources from Arginine.umdnj.eduSources from beyond2000.com

Acute Lymphoblastic Leukemia

• Proliferation of lymphoblasts– anemia, thrombocytopenia, increased WBC– lymphadenopathy/splenomegaly

• B- or T-cell– flow cytometry

• Most common leukemia of childhood

Acute Lymphoblastic Leukemia

Acute Myelogenous Leukemia• Proliferation of myeloblasts

– anemia, thrombocytopenia, increased WBC

• Myeloid, monocytic, RBC, or megakaryocytic– flow cytometry– myeloperoxidase +, TdT-

• Auer rods• Over age of 20

Acute Myelogenous Leukemia

Chronic Myelogenous Leukemia

• One of myeloproliferative diseases (PV, ET)• Proliferation of more mature granulocytes

– normal to increased platelet count– anemia

• Splenomegaly• t(9;22) (bcr-abl) (Philadelphia chromosome)

Chronic Myelogenous Leukemia

Chronic Lymphocytic Leukemia

• Proliferation of small mature B-lymphocytes– flow cytometry (monoclonal Kappa or lambda)

• Lymphadenopathy– relationship to small lymphocytic lymphoma

• May have Ab production • 50% 5-year survival

Chronic Lymphocytic Leukemia

Development of Leukemia in the Bloodstream

Stage 1- Normal Stage 2- Symptoms Stage 3- Diagnosis

Stage 4- Worsening

Stage 5a- Anemia

Stage 5b- Infection

Legend

White Cell

Red Cell

Platelet Blast

Germ Sources from Leukemia, by D. Newton and D. Siegel

ACUTE MYELOID LEUKEMIA ACUTE MYELOID LEUKEMIA (AML)(AML)

• Acute myeloid leukemia (AML) is one of four types of leukemia.

• AML is cancer of the blood-forming tissue (bone marrow). • Normal bone marrow produces red cells, white cells, and

platelets.• AML causes bone marrow to produce too many immature

white blood cells (blast cells).• Suppresses normal blood cell production.

– Anemia, leucopenia, thrombocytopenia

ACUTE MYELOID LEUKEMIA (AML)Clinical Overview

Classification of AML

APL, PML

• Fatigue• Shortness of breath on exertion• Easy bruising• Petechiae• Bleeding in the nose or from the gums• Prolonged bleeding from minor cuts• Recurrent minor infections or poor healing of minor cuts• Loss of appetite or weight loss• Mild fever

Signs and Symptoms

Causation• Genetic changes in AML

• Chromosomal changes lead to activation of oncogenes

• Translocation between chromosomes 8 and 12• Translocation between chromosomes 15 and 17• Deletion of a segment of chromosome 5 or 7

• Genetic factors that predispose an individual to AML• Fanconi’s anemia• Down syndrome• Bloom’s syndrome

Causation• Environmental factors

• Exposure to ionizing radiation• Exposure to benzene• Treatment with alkylating agents or

procarbazine• Treatment with other drugs • Viral oncogenesis (speculative)

• Age• Adults are more likely to develop AML

• Smoking• 20% of AML cases are linked to smoking• Doubles the risk of disease in people older than 60

t(15;17) translocation in AML

Clincal manifestations

• symptoms due to:– marrow failure– tissue infiltration– leukostasis– constitutional symptoms– other (DIC)

• usually short duration of symptoms

Marrow failure• neutropenia: infections, sepsis• anemia: fatigue, pallor• thrombocytopenia: bleeding

Infiltration of tissues/organs• enlargement of liver, spleen, lymph nodes• gum hypertrophy• bone pain• other organs: CNS, skin, testis, any organ

Gum hypertrophy

A

B

C

Chloromas

NEJM 1998

Laboratory features

• WBC usually elevated, but can be normal or low

• blasts in peripheral blood• normocytic anemia• thrombocytopenia• neutropenia• DIC

Auer rods in AML

• ChemotherapyPhase One – Remission induction therapyPhase Two – Remission continuation therapy

• Radiation therapy for certain cases• Bone marrow transplantation

Treatments for AML

• Chemotherapy• Induction therapy

• Initial stage of therapy to eradicate systemic and marrow-localized leukemic cells leading to remission

• Combination of an anthrocycline antibiotic and a cytarabine

• Both prevent DNA synthesis thus stopping growth and leading to their death

• If remission is not achieved with the first round of induction therapy, another round is begun

Treatments

• Post-remission therapy • Consolidation therapy

• Goal is to destroy any undetectable leukemic cells • Many different approaches all of which involve

short doses of intensive therapy

• Maintenance therapy• months to years of less intensive therapy to

prevent further recurrence

Treatments

• Bone marrow transplant• Used as a last resort if 3 rounds of induction

therapy have been unsuccessful• Used as or along with post-remission therapy• Two types of transplants are used

• Autologous• Allogeneic

Treatments

• Radiation therapy• Only used in rare cases where leukemic cells

are centralized in one part of the body

Goal of treatment: Remission• Blood cell counts return to normal• Leukemic cells can no longer be found in blood

or marrow

• If at any time after remission is achieved a relapse occurs the initial treatment may be repeated usually with minor changes in protocol

• If after five years of remission there have been no new outbreaks of leukemic cells the patient is considered cured

After remission

differentiation block

enhancedproliferation

AcuteLeukemia+

Gain of function mutations of tyrosine kinases

eg. FLT3, c-KIT mutations N- and K-RAS mutations BCR-ABL TEL-PDGFR

Loss of function of transcription factors needed for differentiation

eg. AML1-ETO CBF-SMMHC PML-RAR

Two-hit model of leukemogenesis

BLOOD STEM CELLNormal progenitor cell

Leukemic progenitor cell

Leukemic mutation

1% of leukemic cells

99% of leukemic cells

LEUKEMIA

Brian J. P. Huntly & D. Gary Gilliland

Leukemia stem cells could be targeted with chemo

different from that killing leukemic cell

True Tumor involution

Disease remission

Disease recurrence

Conventional

Chemotherapy

Stem cell killing + Conventional Chemotherapy

Stem cell killing

Brian J. P. Huntly & D. Gary Gilliland

To understand the difference between leukemic cell and normal blood cell we shall look into

differentiation related pathways

hematopoietic stem cells

Upregulation PU.1

Downregulation PU.1

common lymphoid progenitor (CLP)

CCAAT/enhancer binding protein-    (C/EBP) α upregulation

Factor interplay fork

Lymphoidcells

Myeloidcells

Erythroidcellscommon myeloid

progenitor (CMP)

Transcription factors involved in normal hematopoiesis

(C/EBP)α

(C/EBP)β

(C/EBP)ε

AML1

GATA1

PU.1

1. Signaling event changes the ratio of PU.1 and GATA proteins in a stem cell.

2. GATA protein inhibit PU.1 blocking its interaction with c-JUN

3. PU.1 inhibitions GATA function through inhibition of GATA DNA binding.

4. GM–CSF and EPO facilitate differentiation along either the myeloidor erythroid pathways

Nature Cancer Review

Upregulation PU.1

Downregulation PU.1

Lymphoidcells

Myeloidcells

Erythroidcells

+ PU.1- GATA = Myeloid

- PU.1+ GATA =Erythroid

PU.1 factorDUAL ROLE OF PU.1 factor

development of a lymphoidprecursor

development of monocytes/macrophages

PU.1 regulates almost every myeloid gene, including GM-CSF receptor, macrophage M-CSF, granulocyte G-CSF

Basal transcription factors

C-Jun positive GATA1, C/EBPnegative

Degradation

http://images.medscape.com/pi/editorial/cmecircle/2002/1023/nimer_intro/slide03.gif

The Future

• Clinical trials• New drug treatments• Vaccines• Immunotherapy• Leukemia type-specific therapy• Gene therapy

– Block encoding instructions of an oncogene– Target the oncoprotein

• Blood and marrow stem cell transplantation– Bone marrow transplantation provides long-term, disease-free

survival among patients in remission