Page 1030 - Hematology_ Basic Principles and Practice ( PDFDrive )

C H A P T E R 58

PATHOBIOLOGY OF ACUTE MYELOID LEUKEMIA

Andrew M. Brunner and Timothy A. Graubert

Acute myeloid leukemia (AML) is a cancer of hematopoietic stem/ of many commonly used chemicals including plastics, dyes, pesti-
progenitor cells, characterized by recurrent genetic and epigenetic cides, solvents, and petroleum products, has been linked to the
alterations. Historically, human leukemias were distinguished accord- subsequent development of AML. This relationship was identified in
ing to clinical and histological features, and subsequently by morphol- the 19th century, when bone marrow aplasia and myeloid leukemia
ogy. More recently, analysis of the AML genome at increasing resolution, were noted among workers exposed to benzene-containing chemicals.
from the level of whole chromosomal changes to individual base pairs, Individuals with occupational benzene exposure have an approxi-
together with an appreciation of epigenetic changes and interactions mately threefold increased relative risk of developing AML. Workplace
within the bone marrow microenvironment, have furthered the under- benzene exposures have decreased significantly since this discovery,
standing of the biology and clinical behavior of this disease. but other sources of benzene exposure remain a concern; for example,
through cigarette smoking. Although cytopenias can occur within
months of benzene exposure, there is a latency of several years between
PHENOTYPE OF ACUTE MYELOID LEUKEMIA benzene exposure and the development of leukemia.
Two classes of chemotherapy drugs are associated with an increased
Normal hematopoiesis is characterized by self-renewal and differen- risk of sAML; cases of AML arising after chemotherapy or radiation
tiation of long-term hematopoietic stem cells (HSCs) to short-term have been historically designated as therapy-related AML (tAML).
HSCs, multipotent progenitors, and common lymphoid and myeloid One class of drugs with clear links to tAML are the topoisomerase II
progenitors. These lineage-committed progenitors further differenti- inhibitors. The most commonly used topoisomerase II inhibitors are
ate to mature lymphoid or myeloid cells, including erythrocytes, anthracyclines, such as doxorubicin, idarubicin, and daunorubicin,
granulocytes, macrophages, and platelets. This process is regulated by and the epipodophyllotoxin etoposide, which are critical components
lineage-specific transcription factors at key points during normal of many treatment regimens for both solid tumors and hematologic
hematopoiesis. Functional analysis of recurrent chromosomal, malignancies. Topoisomerase II is an adeno sine triphosphate-
molecular, and epigenetic alterations in AML has revealed that many dependent enzyme that re-ligates DNA at sites of double-strand breaks
of these lesions cause aberrant activation or derepression of hemato- to manage supercoils; inhibition of this enzyme increases the number
poietic differentiation programs, impacting proliferation, survival, of double-strand breaks. Resolution of these double-strand breaks may
and maturation of myeloid progenitor cells. Consequently, a hallmark occur via error-prone nonhomologous end joining, resulting in accu-
of the AML phenotype is an accumulation of immature myeloid mulation of DNA damage or apoptotic cell death. tAML arising after
precursors. A myeloblast count of 20% or greater distinguishes AML exposure to topoisomerase II inhibitors typically occurs with a latency
from other myeloid malignancies. of 1–3 years, and is often characterized by balanced chromosomal
Historically, leukemias were classified according to morphologic translocations, with the majority involving the Mixed Lineage Leuke-
criteria using the French–American–British (FAB) classification, first mia (MLL) locus on chromosome 11q23. Typical lesions are reciprocal
proposed in 1976. This system classifies AML by the extent of matu- translocations such as t(9;11)(p21;q23) and t(11;19)(q23;p13); other
ration and lineage specificity, ranging from M0 (undifferentiated) to translocations that do not involve the MLL locus have also been
M3 (promyelocytic), M4eo (myelomonocytic with eosinophilia), M6 described, including the t(15;17), t(8;21), and inv(16) rearrange-
(erythroid), or M7 (megakaryocytic). Certain FAB subtypes were ments. The risk of tAML varies based on the chemotherapy dosing
subsequently found to correlate with underlying cytogenetic abnor- schedule, cumulative dose received, additional cytotoxic agents, and
malities, notably M3 with t(15;17), M4eo with inv(16), and M2 with underlying disease characteristics, but generally does not exceed 5% of
t(8;21). As greater understanding of recurrent cytogenetic and now patients treated with topoisomerase II inhibitors.
molecular and epigenetic aberrations have been identified, it has Alkylating agents are the second class of chemotherapy drugs with
become clear that morphology alone is inadequate to fully describe a clear role in the pathogenesis of tAML. The first leukemogenic
the disease spectrum of AML. agents identified in this category were nitrogen mustards. Frequently
implicated drugs in contemporary clinical practice include cyclophos-
phamide, ifosfamide, and melphalan; weaker associations have been
ETIOLOGY OF ACUTE MYELOID LEUKEMIA described with other alkylating agents such as busulfan, thiotepa, and
cisplatin. Alkylating agents create adducts in DNA bases, which are
The majority of patients who develop AML lack any recognized variably mutagenic or cytotoxic. Cytogenetic lesions in alkylator
antecedent disease or predisposition, and for these patients their associated tAML are typically unbalanced, including loss of the long
disease is classified as sporadic or de novo. In these cases, AML arms of chromosomes 5 or 7 [del(5q), del(7q)], or complete loss of
appears to result from the accumulation of spontaneously acquired these chromosomes (−5, −7). The risk of tAML following alkylator
somatic mutations in self-renewing hematopoietic cells. In contrast, exposure is up to 1% per year, but typically has a longer latency (5–7
a diagnosis of secondary AML (sAML) is preceded by a known years), compared with topoisomerase II-associated tAML. The risk
predisposing condition, including environmental exposure, anteced- increases with age and cumulative exposure to these agents. Given the
ent hematologic malignancy, or inherited factors. long latency period, it is likely that alkylating agents cause genomic
instability, which accumulates over time prior to progression to AML.
Consistent with this, heterozygous loss of TP53 appears to be a
Toxins and Exposures common event leading to gain of additional somatic mutations and
development of tAML. In some cases of tAML, small clonal popula-
A number of environmental, occupational, and iatrogenic exposures tions harboring TP53 mutations antedate chemotherapy exposure.
have been identified that contribute to sAML via genotoxic damage TP53 deficiency may confer enhanced fitness on these clones, allowing
to hematopoietic cells. Exposure to benzene, an organic component them to expand under the selective pressure of therapy.

913