Etiology And Pathophysiology Of Aml Biology Essay

Acute myeloid leukemia is a group of heterogenous haematopoietic tumors which are characterized by the clonal proliferation of myeloid precursors, as a consequence of loss of ability to react to normal control mechanisms of cell proliferation and distinction into more mature cells. Worldwide, the overall incidence of ague leukemia harmonizing to WHO is about 4/100,000 population per twelvemonth with 70 % of these instances being AML. [ 1 ] Although the disease occurs at a immature age, the average age of diagnosing is 70 old ages. [ 2 ]

Etiology and Pathophysiology of AML

Hematopoiesis includes all the procedures affecting the proliferation and the distinction of the primogenitor haematopoietic root cells into myelocytes, lymph cells, and megakaryocytes. Creating and keeping appropriate conditions in the microenvironment of the bone marrow is of great importance to continue an effectual haematopoiesis. In AML the distinction of myeloid primogenitor is impaired and the apoptotic mechanisms are inhibited. This apprehension in ripening consequences in uncontrolled proliferation and accretion of myeloid blasts in bone marrow and blood and infiltration of other tissues. Often this leads to haematopoietic inadequacy ( anemia, neutropenia, thrombopenia ) , with or without leucocytosis.

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AML is clinically and biologically a heterogenous group of diseases, as a consequence of great figure of familial and epigenetic events. A great trade of grounds suggests that proto-oncogenes and other growing -promoting cistrons such as those encoding for cytokines or their receptors play an of import function in leukemogenesis. In this evolutionary procedure familial alterations such as chromosomal aberrances or omissions may change the ordinance and map of these proto-oncogenes and growing -promoting cistrons. [ 3 ] Intensive research activity led us to the decision that translocations observed in leukaemia may take topographic point early in the procedure of leukemogenesis since they appear to be stable and balanced within the leukemic ringer. [ 4 ]

Several hazard factors have been associated with the development of AML. These include age, familial upsets, exposure to viruses, to ionising radiation, to chemical and to other occupational jeopardies. [ 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 alterations: omissions or loss of 7q or 5q every bit good as 11q23 chromosomal abnormalcies severally. Additionally exposure to benzene and cigarette smoke are besides possible aetiologic factors. [ 6, 7 ] Despite these associations, at the present clip merely 1-2 % of the diagnosed leukaemia can be attributed to exposure to these agents ( informations from WHO ) .

Categorization of AML

In 1976, a new structural categorization for acute leukaemia was proposed by a on the job commission of French, American and British hematologists. Known as the FAB categorization this system is based on Romanovsky-stained blast morphology and cytochemical discolorations. [ 8 ] Since its debut, the FAB categorization 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 grade of ripening of the peculiar myeloid line of descent involved. The differentiation is based on structural visual aspect of the blasts and their responsiveness with histochemical discolorations. Additionally, immunologic methods have been incorporated into the diagnostic standards for some FAB subgroups. [ 9 ] ( table 1 )

FAB-Type

Monoclonal antibodies for precursor cells

Myeloid markers

Monocyte markers

Terrestrial time

HLA-DR

CD34

CD13

CD33

CD15

CD11

CD14

other

Cytogeneticss

Mo ( minimlly differentiated AML )

+

+

+

11q13

M1 ( myeloid leukaemia without ripening )

+

+

+

+

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

M2 ( myeloid leukaemia with ripening )

+

+

+

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 )

+

+

+

+

+

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

M6 ( erythroid )

Glyco-protein Angstrom

-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 leucocyte antigen D-related ( from “ Cancer Medicine ” )

Over the old ages, many big clinical surveies have highlighted the value of cytogenetic abnormalcies in ague leukaemia, asking the alteration of FAB categorization. Because of increasing acknowledgment of the importance of familial events to the diagnosing and intervention of ague leukaemia, a new categorization was proposed from WHO in 2001. ( Table 2 ) This categorization incorporates familial aberrances and immunology as major specifying characteristics in add-on to morphology and lowers the threshold for the diagnosing 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 diagnosing of AML is made irrespective of the per centum of bone marrow blasts.

WHO categorization of AML

Acute myeloid leukemia with perennial familial abnormalcies

Acute myeloid leukemia with T ( 8 ; 21 ) ( q22 ; q22 ) ; ( AML1ETO )

Acute myeloid leukemia with unnatural bone marrow eosinophils inv ( 16 ) ( p13q22 ) or T ( 16 ; 16 ) ( p13 ; q22 )

Acute promyelocytic leukemia ( AML with T ( 15 ; 17 ) ( q22 ; q12 ) ( PML/RARa ) and discrepancies

Acute myeloid leukemia with 11q23 ( MLL ) abnormalcies

Acute myeloid leukemia with multilineage dysplasia

Following a myelodysplastic syndrome or myelodysplastic/myeloprolife-rative upset

Without antecedent myelodysplastic syndrome

Acute myeloid leukemia and myelodysplastic syndromes, therapy related

Alkylating agent-related

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

Other types

Acute myeloid leukemia non otherwise categorised

Acute myeloid leukemia minimally differentiated

Acute myeloid leukemia without ripening

Acute myeloid leukemia with ripening

Acute myelomonocytic leukemia

Acute monoblastic and monocytic leukemia

Acute erythroid leukemia

Acute megakaryoblastic leukemia

Acute basophilic leukemia

Acute panmyelosis with myelofibrosis

Myeloid sarcoma

Table 2: WHO categorization of AML

Since 2001, considerable advancement in understanding the biological science of the disease has been made. The find of many molecular abnormalcies in myeloid tumors and the demand for a common linguistic communication between clinicians and research lab research workers has led to the publication of another alteration of the categorization. It has has been published as portion of the 4th edition [ 10 ] of the WHO, in which new classs but besides new probationary entities have been incorporated. ( Table 3 )

Acute myeloid leukaemia and related tumors

Acute myeloid leukemia with perennial familial abnormalcies

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

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

Acute promyelocytic leukemia 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

Probationary AML with mutated NPM1

Probationary AML with mutated CEBPA

AML with myelodysplasia-related alterations

Therapy related myeloid tumors

AML non otherwise categorised ( NOS )

AMLwith minimum distinction

AML without ripening

Acute myeloid leukemia with ripening

Acute myelomonocytic leukemia

Acute monoblastic and monocytic leukemia

Acute erythroid leukemia

Acute megakaryoblastic leukemia

Acute basophilic leukemia

Acute panmyelosis with myelofibrosis

Myeloid sarcoma

Myeloid proliferations related to Down syndrome

Transient unnatural myelopoiesis

Myeloid leukaemia associated with Down syndrome

Blastic plasmacytoid dendritic cell tumor

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

1.2 Two-hit theoretical account of AML

The pathogenesis of AML requires series of familial events. [ 11 ] The specific mutational events required for this patterned advance are non presently good defined. Based on experimental informations from mouse bone marrow organ transplant theoretical accounts, G.Gililland [ 12 ] proposed the “ two-hit theoretical account ” of leukemogenesis. Harmonizing to this hypothesis AML is the effect of coaction of at least two categories of mutants:

category I mutants: the first type of familial lesion involves mutants that disturb the signal transduction tracts, favoring the proliferation and/or the endurance of the cells. Already recognized mutants belonging to this class are:

mutants taking to uninterrupted activation of FLT-3 receptor.

FLT-3 is a transmembrane receptor and belongs in PDGFR subfamily ( category III ) of tyrosine kinase receptors which besides include PDGFRI± , PDGFRI? , FMS and KIT [ 13, 14 ] . These receptors present common construction: a ) 5 extracellular Ig spheres, B ) a transmembrane sphere, degree Celsius ) a juxtamembrane sphere and vitamin D ) an intracellular tyrosine kinase sphere ( TK ) . [ 15 ] FLT-3 receptor is expressed in primogenitor root cells and dramas function in endurance, proliferation and distinction through signal transduction tracts like Ras/Raf/Mek/Erk/STAT. [ 13 ] In AML two types of mutants have been recognized:

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

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

Acute myeloid leukemia ( AML ) is a group of heterogenous haematopoietic tumors which are characterized by the clonal proliferation of myeloid precursors, as a consequence of loss of ability to react to normal control mechanisms of cell proliferation and distinction into more mature cells. Worldwide, the overall incidence of ague leukemia harmonizing to WHO is about 4/100,000 population per twelvemonth with 70 % of these instances being AML. [ 1 ] Although the disease occurs at a immature age, the average age of diagnosing is 70 old ages. [ 2 ]

Etiology and Pathophysiology of AML

Hematopoiesis includes all the procedures affecting the proliferation and the distinction of the primogenitor haematopoietic root cells into myelocytes, lymph cells, and megakaryocytes. Creating and keeping appropriate conditions in the microenvironment of the bone marrow is of great importance to continue an effectual haematopoiesis. In AML the distinction of myeloid primogenitor is impaired and the apoptotic mechanisms are inhibited. This apprehension in ripening consequences in uncontrolled proliferation and accretion of myeloid blasts in bone marrow and blood and infiltration of other tissues. Often this leads to haematopoietic inadequacy ( anemia, neutropenia, thrombopenia ) , with or without leucocytosis.

AML is clinically and biologically a heterogenous group of diseases, as a consequence of great figure of familial and epigenetic events. A great trade of grounds suggests that proto-oncogenes and other growing -promoting cistrons such as those encoding for cytokines or their receptors play an of import function in leukemogenesis. In this evolutionary procedure familial alterations such as chromosomal aberrances or omissions may change the ordinance and map of these proto-oncogenes and growing -promoting cistrons. [ 3 ] Intensive research activity led us to the decision that translocations observed in leukaemia may take topographic point early in the procedure of leukemogenesis since they appear to be stable and balanced within the leukemic ringer. [ 4 ]

Several hazard factors have been associated with the development of AML. These include age, familial upsets, exposure to viruses, to ionising radiation, to chemical and to other occupational jeopardies. [ 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 alterations: omissions or loss of 7q or 5q every bit good as 11q23 chromosomal abnormalcies severally. Additionally exposure to benzene and cigarette smoke are besides possible aetiologic factors. [ 6, 7 ] Despite these associations, at the present clip merely 1-2 % of the diagnosed leukaemia can be attributed to exposure to these agents ( informations from WHO ) .