Etiology And Pathophysiology Of Aml Biology Essay

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Acute myeloid leukaemia is a group of heterogeneous hematopoietic neoplasms which are characterized by the clonal proliferation of myeloid precursors, as a result of loss of ability to respond to normal control mechanisms of cell proliferation and differentiation into more mature cells. Worldwide, the overall incidence of acute leukaemia according to WHO is about 4/100,000 population per year with 70% of these cases being AML.[1] Although the disease occurs at a young age, the median age of diagnosis is 70 years. [2]

Etiology and Pathophysiology of AML

Hematopoiesis includes all the processes involving the proliferation and the differentiation of the progenitor hematopoietic stem cells into myelocytes, lymphocytes, and megakaryocytes. Creating and maintaining appropriate conditions in the microenvironment of the bone marrow is of great importance to preserve an effective hematopoiesis. In AML the differentiation of myeloid progenitor is impaired and the apoptotic mechanisms are inhibited. This arrest in maturation results in uncontrolled proliferation and accumulation of myeloid blasts in bone marrow and blood and infiltration of other tissues. Often this leads to hematopoietic insufficiency (anaemia, neutropenia, thrombocytopenia), with or without leukocytosis.

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AML is clinically and biologically a heterogeneous group of diseases, as a result of great number of genetic and epigenetic events. A great deal of evidence suggests that proto-oncogenes and other growth -promoting genes such as those encoding for cytokines or their receptors play an important role in leukemogenesis. In this evolutionary process genetic changes such as chromosomal aberrations or deletions may alter the regulation and function of these proto-oncogenes and growth -promoting genes.[3] Intensive research activity led us to the conclusion that translocations observed in leukemias may take place early in the process of leukemogenesis since they appear to be stable and balanced within the leukemic clone.[4]

Several risk factors have been associated with the development of AML. These include age, genetic disorders, exposure to viruses, to ionizing radiation, to chemical and to other occupational hazards.[5] Previous exposure to cytotoxic therapy with alkylating agents and topoisomerase II inhibitors, has been reported to increase the incidence of AML, and has been related to specific cytogenic changes: deletions or loss of 7q or 5q as well as 11q23 chromosomal abnormalities respectively. Additionally exposure to benzene and cigarette smoking are also possible etiological factors.[6, 7] Despite these associations, at the present time only 1-2% of the diagnosed leukemias can be attributed to exposure to these agents (data from WHO).

Classification of AML

In 1976, a new morphologic classification for acute leukemias was proposed by a working committee of French, American and British haematologists. Known as the FAB classification this system is based on Romanovsky-stained blast morphology and cytochemical stains.[8] Since its introduction, the FAB classification has been widely accepted internationally. It demands the presence of 30% of blasts in the bone marrow and divides the AML into eight subtypes depending on the degree of maturation of the particular myeloid lineage involved. The distinction is based on morphologic appearance of the blasts and their reactivity with histochemical stains. Additionally, immunologic methods have been incorporated into the diagnostic criteria for some FAB subgroups.[9] (table 1)

FAB-Type

Monoclonals for precursor cells

Myeloid markers

Monocyte markers

TDt

HLA-DR

CD34

CD13

CD33

CD15

CD11

CD14

other

Cytogenetics

Mo (minimlly differentiated AML)

±

+

+

+

±

±

-

-

11q13

M1 (myeloid leukemia without maturation)

±

+

+

+

+

-

±

-

-5,-7,-17, del 3p+21,+8

M2 (myeloid leukemia with maturation)

-

+

-

-

+

+

±

-

t(8;21), del 3p or inv3, -5,-7 t(6;9),+8

M3 (promyelocytic APL)

-

-

-

-

+

±

-

-

t(15;17)

M4 (myelomonocytic)

-

+

-

-

+

+

+

+

inv(16) or -16q, t(16;16) occt(8;21), -5, -7 t(6;9)

M5 (monocytic)

-

+

-

±

+

+

+

+

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t(9;11)(p21;p23) +8

M6 (erythroid)

-

±

-

±

±

-

±

-

Glyco-protein A

-5q,-5,-7,-3,+8

M7 (megakaryocytic)

-

+

+

-

±

-

-

-

Platelet glyco-protein

inv or del3 +8,+21

Table 1: FAB classificationof AML

Tdt-terminal deoxinucleotide transferase, HLA-DR-human leukocyte antigen D-related (from "Cancer Medicine")

Over the years, many large clinical studies have highlighted the value of cytogenetic abnormalities in acute leukemias, necessitating the revision of FAB classification. Because of increasing recognition of the importance of genetic events to the diagnosis and treatment of acute leukemias, a new classification was proposed from WHO in 2001. (Table 2) This classification incorporates genetic aberrations and immunology as major defining features in addition to morphology and lowers the threshold for the diagnosis of AML from 30% to 20% blasts in the peripheral blood and/or the bone marrow aspirate. Exceptions include AML with t(8;21), inv(16) or t(15;17), in which the diagnosis of AML is made regardless of the percentage of bone marrow blasts.

WHO classification of AML

Acute myeloid leukaemia with recurrent genetic abnormalities

Acute myeloid leukaemia with t(8;21)(q22;q22);(AML1ETO)

Acute myeloid leukaemia with abnormal bone marrow eosinophils inv(16)(p13q22) or t(16;16)(p13;q22)

Acute promyelocytic leukaemia (AML with t(15;17)(q22;q12)(PML/RARa) and variants

Acute myeloid leukaemia with 11q23 (MLL) abnormalities

Acute myeloid leukaemia with multilineage dysplasia

Following a myelodysplastic syndrome or myelodysplastic/myeloprolife-rative disorder

Without antecedent myelodysplastic syndrome

Acute myeloid leukaemia and myelodysplastic syndromes, therapy related

Alkylating agent-related

Topoisomerase type II inhibitor-related (some may be lymphoid)

Other types

Acute myeloid leukaemia not otherwise categorised

Acute myeloid leukaemia minimally differentiated

Acute myeloid leukaemia without maturation

Acute myeloid leukaemia with maturation

Acute myelomonocytic leukaemia

Acute monoblastic and monocytic leukaemia

Acute erythroid leukaemia

Acute megakaryoblastic leukaemia

Acute basophilic leukaemia

Acute panmyelosis with myelofibrosis

Myeloid sarcoma

Table 2: WHO classification of AML

Since 2001, considerable progress in understanding the biology of the disease has been made. The discovery of many molecular abnormalities in myeloid neoplasms and the need for a common language between clinicians and laboratory investigators has led to the publication of another revision of the classification. It has has been published as part of the 4th edition[10] of the WHO, in which new categories but also new provisional entities have been incorporated. (Table 3)

Acute myeloid leukemia and related neoplasms

Acute myeloid leukaemia with recurrent genetic abnormalities

AML with t(8;21)(q22;q22); RUNX1-RUNX1T1

AML with inv(16)(p13q22) or t(16;16)(p13;q22); CBFB-MYH11

Acute promyelocytic leukaemia with t(15;17)(q22;q12); PML/RARa

AML with t(9;11)(p22;q23) MLLT3-MLL

AML with t(6;9)p(23;24); DEK-NUP214

AML with inv(3)(q21q26.2) or t(3.3)(q21;q26.2); RPN1-EVI1

AML (megakaryoblastic) with t(1:22)(p13;q13); RBM15-MKL1

Provisional AML with mutated NPM1

Provisional AML with mutated CEBPA

AML with myelodysplasia-related changes

Therapy related myeloid neoplasms

AML not otherwise categorised (NOS)

AMLwith minimal differentiation

AML without maturation

Acute myeloid leukaemia with maturation

Acute myelomonocytic leukaemia

Acute monoblastic and monocytic leukaemia

Acute erythroid leukaemia

Acute megakaryoblastic leukaemia

Acute basophilic leukaemia

Acute panmyelosis with myelofibrosis

Myeloid sarcoma

Myeloid proliferations related to Down syndrome

Transient abnormal myelopoiesis

Myeloid leukemia associated with Down syndrome

Blastic plasmacytoid dendritic cell neoplasm

Table 3: WHO classification of AML 4th edition (2008)

1.2 Two-hit model of AML

The pathogenesis of AML requires series of genetic events.[11] The specific mutational events required for this progression are not currently well defined. Based on experimental data from mouse bone marrow transplantation models, G.Gililland[12] proposed the "two-hit model" of leukemogenesis. According to this hypothesis AML is the consequence of collaboration of at least two classes of mutations:

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class I mutations : the first type of genetic lesion involves mutations that disturb the signal transduction pathways, favouring the proliferation and/or the survival of the cells. Already recognised mutations belonging to this category are:

mutations leading to continuous activation of FLT-3 receptor.

FLT-3 is a transmembrane receptor and belongs in PDGFR subfamily (class III) of tyrosine kinase receptors which also include PDGFRα, PDGFRβ, FMS and KIT[13, 14]. These receptors present common structure: a) 5 extracellular immunoglobulin domains, b) a transmembrane domain, c)a juxtamembrane domain and d) an intracellular tyrosine kinase domain (TK).[15] FLT-3 receptor is expressed in progenitor stem cells and plays role in survival, proliferation and differentiation through signal transduction pathways like Ras/Raf/Mek/Erk/STAT. [13] In AML two types of mutations have been recognized:

mutations of the internal tandem duplication (ITD)(FLT3-ITD) seen in 23% of patients with AML.[13]

point mutations which involve usually codon 835 )(FLT3-Asp835) of the kinase domain and is found in 8-12% of the AML patients.[13]

Acute myeloid leukaemia (AML) is a group of heterogeneous hematopoietic neoplasms which are characterized by the clonal proliferation of myeloid precursors, as a result of loss of ability to respond to normal control mechanisms of cell proliferation and differentiation into more mature cells. Worldwide, the overall incidence of acute leukaemia according to WHO is about 4/100,000 population per year with 70% of these cases being AML.[1] Although the disease occurs at a young age, the median age of diagnosis is 70 years. [2]

Etiology and Pathophysiology of AML

Hematopoiesis includes all the processes involving the proliferation and the differentiation of the progenitor hematopoietic stem cells into myelocytes, lymphocytes, and megakaryocytes. Creating and maintaining appropriate conditions in the microenvironment of the bone marrow is of great importance to preserve an effective hematopoiesis. In AML the differentiation of myeloid progenitor is impaired and the apoptotic mechanisms are inhibited. This arrest in maturation results in uncontrolled proliferation and accumulation of myeloid blasts in bone marrow and blood and infiltration of other tissues. Often this leads to hematopoietic insufficiency (anaemia, neutropenia, thrombocytopenia), with or without leukocytosis.

AML is clinically and biologically a heterogeneous group of diseases, as a result of great number of genetic and epigenetic events. A great deal of evidence suggests that proto-oncogenes and other growth -promoting genes such as those encoding for cytokines or their receptors play an important role in leukemogenesis. In this evolutionary process genetic changes such as chromosomal aberrations or deletions may alter the regulation and function of these proto-oncogenes and growth -promoting genes.[3] Intensive research activity led us to the conclusion that translocations observed in leukemias may take place early in the process of leukemogenesis since they appear to be stable and balanced within the leukemic clone.[4]

Several risk factors have been associated with the development of AML. These include age, genetic disorders, exposure to viruses, to ionizing radiation, to chemical and to other occupational hazards.[5] Previous exposure to cytotoxic therapy with alkylating agents and topoisomerase II inhibitors, has been reported to increase the incidence of AML, and has been related to specific cytogenic changes: deletions or loss of 7q or 5q as well as 11q23 chromosomal abnormalities respectively. Additionally exposure to benzene and cigarette smoking are also possible etiological factors.[6, 7] Despite these associations, at the present time only 1-2% of the diagnosed leukemias can be attributed to exposure to these agents (data from WHO).