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1376 Part X: Malignant Myeloid Diseases Chapter 88: Acute Myelogenous Leukemia 1377

MOLECULAR PATHOGENESIS AML cases represent incomplete eradication of founder clones and not
The Leukemia Stem Cell emergence of unrelated clones. 94
AML results from a series of somatic mutations in a primitive hemato-
poietic multipotential progenitor cell or, very occasionally, a more dif- Role of Telomeres
ferentiated, more lineage-restricted progenitor cell. 83,84 Some cases of AML with multiple chromosome aberrations is always characterized
monocytic leukemia, promyelocytic leukemia, and AML in younger by critically short telomeres. Age-related critical telomere shortening
individuals may arise in a progenitor cell with lineage restrictions may have a role in generating chromosome instability in AML patho-
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(progenitor cell leukemia). 85–87 Other morphologic phenotypes and genesis. Leukemic cells show variable reduction in length of telomeric
older patients likely have a disease that originates in a primitive mul- DNA, and telomere length in blood cells during remission is greater. 96
tipotential cell. In the latter case, all myeloid blood cell lineages can be
derived from the leukemic stem cell because it retains the ability for Somatic Mutations
some degree of differentiation and maturation (Chap. 83). Because the Somatic mutation results from a chromosomal translocation in a large
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T lymphocytes, B lymphocytes, and natural killer cells in cases of AML, fraction of patients. The translocation results in rearrangement of
often, have not carried a cytogenetic abnormality as did the myeloid a critical region of a protooncogene. Fusion of portions of two genes
cells, claims of origin in the pluripotential lymphohematopoietic cell often does not prevent the processes of transcription and translation;
have been ambiguous. The most compelling data indicate that the bulk of thus, the fusion oncogene encodes a fusion protein that, because of its
AML cases arise from one of two predominant CD34+ cell populations: abnormal structure, disrupts a normal cell pathway and predisposes to a
CD34+CD45RA+CD38–CD90– (multipotential myeloid progenitor) or malignant transformation of the cell. The mutant protein product often
CD34+CD38+CD45RA+CD110+ (granulocyte-monocyte progenitor). is a transcription factor or an element in the transcription pathway that
Both of these cell populations correspond to normal hematopoietic pro- disrupts the regulatory sequences controlling growth rate or survival
genitor cells and not the normal pluripotential lymphohematopoietic of blood cell progenitors and their differentiation and maturation. 97–99
stem cell. 86,88 This finding was confirmed by showing that the two leu- Examples of genes often mutated are core binding factor (CBF), retinoic
kemic cell populations were more similar to the corresponding normal acid receptor-α (RAR-α), HOX family, mixed-lineage leukemia (MLL),
progenitor populations than to pluripotential lymphohematopoietic and others. CBF has two subunits: CBF-β and runt-related transcription
stem cells by microarray gene expression analysis. The AML stem cell factor 1(RUNX1, formerly AML1). Approximately 10 percent of AML
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arises from somatic mutations in one of these populations in most, but cases have translocations involving one or the other of these latter two
not all, cases of AML. Because progenitor cells are not self-renewing, genes (CBF-β and RUNX1), although the percentage varies depend-
the somatic mutations transform the normal progenitor cell to an AML ing on the patient’s age at onset. In patients younger than age 50 years,
stem cell capable of sustaining the disease and transplanting it into the frequency is approximately 20 percent. In patients older than age
immunosuppressed (NOD/SCID/IL2Rγ null) mice. 50 years, the frequency is approximately 6 percent. CBF activates genes
involved in myeloid and lymphoid differentiation and maturation. These
primary mutations are not sufficient to cause AML. Additional activat-
Preleukemic Stem Cells ing mutations, for example, in hematopoietic tyrosine kinases Fms-like
There is, also, experimental evidence that some cases of AML can arise tyrosine kinase (FLT)3 and KIT or in N-RAS and K-RAS, are required
from the accumulation of genetic and epigenetic changes in normal to induce a proliferative advantage in the affected primitive cell. Other
pluripotential HSCs. Through single-cell analysis, it has been shown protooncogene mutations that occur in leukemic cells involve FES, FOS,
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that clonal progression of multiple mutations occurs in the HSC of GATA-1, JUN B, MPL, MYC, p53, PU.1, RB, WT1 (Wilms tumor 1),
some AML patients. These HSCs have been given the name “preleu- WNT, NPM1, CEPBA (CCAAT-enhancer binding protein A), and other
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kemic HSCs” and it is proposed that AML progresses from such cells genes. Their interaction with loss-of-function mutations in hematopoi-
carrying founder mutations. These are thought to form a reservoir after etic transcription factors probably causes the acute leukemia phenotype
therapy that can lead to relapse. An HSC with DNA methyltransferase characterized by a disorder of proliferation, programmed cell death,
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3A (DNMT3A) mutants was found to have multilineage repopulation differentiation, and maturation. Because the mutant stem or early pro-
advantage over nonmutated HSCs in xenografts, establishing their iden- genitor cell can proliferate and retains the capability to differentiate, a
tity as preleukemic HSCs. These cells can be found in remission marrow wide variety of phenotypes can emerge from a leukemic transformation.
samples of patients with AML. Genes that regulate DNA methylation
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such as DNMT3A, ten-eleven translocation (TET) 2, and isocitrate
dehydrogenase (IDH) 1 and 2 promote self-renewal and block differ- EFFECT OF MOLECULAR AND CYTOGENETIC
entiation of stem and progenitor cells. Acquisition of these mutations MARKERS ON DISEASE PROGRESSION AND
in an HSC can lead to their clonal expansion resulting in a preleukemia
stem cell population. 92 THERAPEUTIC RESPONSIVENESS
Gene Markers
Mutational History AML is a heterogeneous disease, and the extent to which cytogenetic
Genome sequencing in AML cells shows that most mutations occur at and molecular markers define severity and influence treatment deci-
random before acquisition of the initiating driver mutation, giving each sions is a rapidly changing arena of investigation as a result of continued
clone a mutational history. The founding clone may acquire additional refinements in correlating individual or a combination of mutations on
mutations, yielding subclones that contribute to disease progression disease progression. Using molecular markers to predict disease course
or relapse. When copy number aberrations and copy-neutral loss-of- in AML is complicated because these are incompletely determined,
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heterozygosity gene mutation profiles are analyzed in AML cases at and they often interact. Several risk scores based on chromosome and
diagnosis and at relapse, the relapsed leukemia always reflects reemer- molecular markers have integrated factors such as age and white blood
gence of the founder clone. In persistent AML cases, sometimes two cell (WBC) count into the scoring systems. 100,101 Others have identified
coexisting dominant clones can be seen, one chemotherapy-sensitive common gene signatures that can be independent predictors of disease
and one chemotherapy-resistant, suggesting that refractory or relapsed progression or therapeutic response and provide a structure for risk

Kaushansky_chapter 88_p1373-1436.indd 1376 9/21/15 11:00 AM