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Acute Myelogenous Leukemia

Acute myelogenous leukemias affect primarily adults, peaking in incidence between the ages of 15 and 39 years, but are also observed in older adults and children. AML is quite

heterogeneous, reflecting the complexities of myeloid cell differentiation.


Most AMLs are associated with acquired genetic alterations that inhibit terminal myeloid differentiation. As a result, normal marrow elements are replaced by relatively undifferentiated

blasts exhibiting one or more types of early myeloid differentiation. The replication rate of these blasts is actually lower than that of normal myeloid progenitors, highlighting the

pathogenic importance of blocked maturation and increased survival.

Specific recurrent chromosomal aberrations, including translocations, are seen in a high fraction of AMLs and tend to disrupt genes encoding transcription factors needed for normal

myeloid differentiation. For example, the most common chromosomal rearrangements, t(8;21) and inv(16), involve genes that normally encode two subunits, CBF1a and CBF1b, of a

single heterodimeric transcription factor. Both the t(8;21) and the inv(16) result in the formation of chimeric genes encoding fusion proteins with so-called dominant negative activity,

meaning they interfere with the function of the normal CBF1a/CBF1b heterodimer. Myeloid progenitors harboring such aberrations thus give rise to daughter cells exhibiting a partial or

complete block in terminal differentiation. A deficit of CBF1a/CBF1b activity is not sufficient to cause leukemia, however, as "knockout" mice lacking either CBF1a or CBF1b, or

"knock-in" mice expressing the fusion proteins created by the t(8;21) or inv(16),[66] succumb to hematopoietic failure. In such animals, the "blocked" progenitors die rather than

undergoing transformation, indicating that other aberrations must collaborate with defects in critical transcription factors to produce AML.

An example of such a pathogenic collaboration underlies a form of AML, acute promyeloctyic leukemia, associated with a (15;17) chromosomal translocation. This translocation produces

a fusion gene encoding a portion of a transcription factor, retinoic acid receptor-a (RARa), fused to a portion of another protein, PML. RARa normally activates transcription, but when

fused to PML, it is converted to a repressor that turns off genes required for full and complete myeloid differentiation. In addition to the t(15;17), acute promyelocytic leukemia cells also

frequently acquire point mutations in FLT3, a tyrosine kinase, that result in its constitutive activation.[67] As you will recall from Chapter 3 , tyrosine kinases produce signals that promote

cellular proliferation and survival, activities that synergize with the block in differentiation produced by the RARa-PML fusion protein. This pathogenic collaboration has been proven in

mouse models, in which coexpression of a RARa-PML fusion protein and activated forms of FLT3 produce the rapid onset of AML. It is believed that distinct, but pathogenically

analogous, sets of synergistic genetic "hits" underlie other forms of AML.[68]

In all AMLs, the accumulation of proliferating neoplastic myeloid precursor cells in the marrow suppresses remaining normal hematopoietic progenitor cells by physical replacement as

well as by other unknown mechanisms. The failure of normal hematopoiesis results in anemia, neutropenia, and thrombocytopenia, which cause most of the major clinical complications of

AML. Therapeutically, the aim is to clear the bone marrow of the leukemic clone, thus permitting resumption of normal hematopoiesis. This can be accomplished by treatment with

cytotoxic drugs or, in the specific case of acute promyelocytic leukemia, by overcoming the block in differentiation with pharmacologic doses of retinoic acid.


In the most widely used system in current use, the revised FAB classification ( Table 14-8A ), AML is divided into eight (M0 to M7) categories.[69] This scheme takes into account both the

degree of maturation (M0 to M3) and the lineage of the leukemic blasts (M4 to M7). Histochemical stains for peroxidase, specific esterase, and nonspecific esterase, and immunostains for

myeloid specific antigens (see Table 14-8A ) play important roles in defining the type of myeloid differentiation that blasts exhibit.

A recently proposed WHO classification for AML ( Table 14-8B ) retains the FAB categories M0 to M7 but also creates special categories for AMLs associated with particular

chromosomal aberrations (e.g., the t(15;17), t(8;21), inv(16), or 11q23 rearrangements), which arise after prior chemotherapy or follow a myelodysplastic syndrome.[11] This classification

thus attempts to define forms of AML according to molecular pathogenesis and outcome. Given the increasing role of cytogenetic and molecular features in directing therapy, a further shift

toward molecular genetic classifications of AML seems inevitable and desirable.


The diagnosis of AML is based on finding that myeloid blasts make up more than 20% of the cells in the marrow.Several types of myeloid blasts are recognized, but more than one

type of blast, or blasts with hybrid features, can be seen in individual patients. Myeloblastshave delicate nuclear chromatin, two to four nucleoli, and more voluminous cytoplasm than

lymphoblasts ( Fig. 14-28A ). The cytoplasm often contains fine, azurophilic, peroxidase-positive granules. Distinctive red-staining peroxidase-positive structures called Auer rods, which

represent abnormal azurophilic granules, are present in many cases and are particularly numerous in AML associated with the t(15;17) (acute promyelocytic leukemia) ( Fig. 14-29A ). The

presence of Auer rods is taken to be definitive evidence of myeloid differentiation. Monoblasts( Fig. 14-29B ) often have folded or lobulated nuclei, lack Auer rods, and are peroxidase

negative and nonspecific esterase positive. In some AMLs, blasts exhibit megakaryocytic differentiation, which is often accompanied by marrow fibrosis caused by the release of

fibrogenic cytokines. Rarely, the blasts of AML show evidence of erythroid differentiation (erythroblasts).

The number of leukemic cells in the peripheral blood is highly variable. Blast counts can be more than 100,000 cells per microliter but are under 10,000

TABLE 14-8A-- Revised FAB Classification of Acute Myelogenous Leukemias


Incidence (% of

AML) Marrow Morphology/Comments

M0 Minimally differentiated AML 23% Blasts lack definitive cytologic and cytochemical markers of myeloblasts (e.g., myeloperoxidase negative) but

express myeloid lineage antigens and resemble myeloblasts ultrastructurally.

M1 AML without differentiation 20% Very immature, but ³3% of blasts are peroxidase positive; few granules or Auer rods and little maturation beyond

the myeloblast stage.

M2 AML with maturation 3040% Full range of myeloid maturation through granulocytes; Auer rods present in most cases; often associated with the t


M3 Acute promyelocytic leukemia 510% Most cells are hypergranular promyelocytes, often with many Auer rods per cell; patients are younger (median age

35 to 40 years); high incidence of DIC; strong association with the t(15;17).

M4 Acute myelomonocytic leukemia 1520% Myelocytic and monocytic differentiation evident; myeloid elements show range of maturation; monoblasts are

positive for nonspecific esterases; subset associated with the inv(16).

M5 Acute monocytic leukemia 10% In M5a subtype, monoblasts (peroxidase-negative, nonspecific esterase-positive) and promonocytes predominate

in marrow and blood; in M5b subtype, mature monocytes predominate in the peripheral blood; M5a and M5b

occur in older patients; characterized by high incidence of organomegaly, lymphadenopathy, and tissue infiltration.

M6 Acute erythroleukemia 5% Dysplastic erythroid precursors (some megaloblastoid, others with giant or multiple nuclei) predominate, and

within the non-erythroid cells, >30% are myeloblasts; seen in advanced age; makes up 1% of de novo AML and

20% of therapy-related AML.

M7 Acute megakaryocytic leukemia 1% Blasts of megakaryocytic lineage predominate; blasts react with platelet-specific antibodies directed against GPIIb/

IIIa or vWF; myelofibrosis or increased marrow reticulin seen in most cases.

DIC, disseminated intravascular coagulation; vWF, von Willebrand factor.

TABLE 14-8B-- Proposed WHO Classification of Acute Myelogenous Leukemias

Class Prognosis

Date: 2016-04-22; view: 1497

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