Page 1032 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 58 Pathobiology of Acute Myeloid Leukemia 915

fashion and is associated with mutations in a number of ribosomal Inherited mutations in GATA2 cause a spectrum of disorders with
proteins. Defects in ribosome function result in anemia early in life overlapping features, including Emberger syndrome (OMIM 614038)
and patients with DBA may have characteristic skeletal anomalies, and immunodeficiency 21 (IMD21) (OMIM 614172), also described
including craniofacial defects, and at times the classic triphalangeal as monocytopenia with susceptibility to mycobacterial, fungal, and
thumb; this anemia is often steroid responsive but many eventually papillomavirus infection and myelodysplasia (MonoMAC syndrome)
require chronic transfusional support and hematopoietic cell trans- or dendritic cell, monocyte, B-lymphocyte and natural killer lympho-
plantation. AML can occur in up to 20% of patients and typically cyte deficiency (DCML). Patients with IMD21 have decreased
occurs after 40 years of age. monocyte counts, natural killer and B-cell deficiency, and are at
Congenital amegakaryocytic thrombocytopenia (CAMT) (OMIM increased risk of viral and nontuberculous mycobacterial infections.
604498) and thrombocytopenia with absent radii (TAR) (OMIM Emberger syndrome patients have a similar presentation, but also
274000) syndrome are both characterized by hypoplastic thrombo- have deafness and lymphedema, and often develop pancytopenia.
cytopenia. CAMT is inherited in an autosomal recessive manner via AML or MDS arises in approximately 70% of carriers and is associ-
mutations in the MPL gene, which encodes the receptor for throm- ated with cooperating genetic events, such as mutations in ASXL1 or
bopoietin (TPO). Patients have concomitant elevations in serum hemizygous deletions involving chromosome 7.
TPO levels, and thrombocytopenia from birth, which typically
progresses to aplasia. CAMT is associated with an increased incidence
of AML, typically in the second decade of life. While CAMT does GENETIC AND EPIGENETIC ALTERATIONS IN ACUTE
not have phenotypic manifestations outside of thrombocytopenia, MYELOID LEUKEMIA
TAR syndrome is also associated with thrombocytopenia at birth, as
well as characteristic absence of the radii. TAR syndrome has been AML is characterized by a large number of recurrent cytogenetic,
associated with mutations in RBM8A, which is involved in messenger molecular, and epigenetic modifications that illustrate the patho-
RNA (mRNA) splicing. The thrombocytopenia in TAR syndrome physiologic role of acquired somatic alterations affecting specific gene
often improves over time; both acute lymphoblastic leukemia and products. These mutations have been incorporated into strategies for
AML have been reported among patients with this rare disorder. prognostic stratification and risk-adapted treatment, in addition to
Down syndrome, caused by trisomy 21, is associated with an providing a framework for targeted therapy. The World Health
approximately 10–20-fold elevated relative risk of AML and MDS Organization (WHO) classification now recognizes a number of
compared with the general population, and in particular an increased recurrent genetic abnormalities, including balanced translocations
risk for acute megakaryocytic leukemia, FAB M7. Infants with Down and inversions, as defining features of AML.
syndrome may experience transient abnormal myelopoiesis (TAM), Early understanding of the pathogenesis of AML suggested a
where circulating peripheral blood blasts are seen and may be accom- model where AML occurred in the setting of acquired mutations in
panied by hepatic dysfunction, effusions, and rash; this occurs in two pathways: class I mutations, which activate cell proliferation and
approximately 10% of these patients. The majority of TAM cases survival pathways, and class II mutations, which block normal
harbor somatic mutations in GATA1, resulting in altered function of mechanisms of differentiation. This arose out of the identification of
this transcription factor that plays an important role in hematopoietic mutations that commonly arose together or were both required in
cell maturation, particularly in the megakaryocyte lineage. Decreased mouse models to produce leukemia, such as class I mutations in
GATA1 expression results in megakaryocyte proliferation. Indeed, up cytokine signaling pathways, and class II mutations in hematopoietic
to 30% of persons with TAM will progress to AML, commonly acute transcription factors. However, this model does not account for the
megakaryocytic leukemia. The development of AML in patients with wide spectrum of more recently described somatic alterations, nor do
Down syndrome likely relates both to acquired somatic mutations, all patients carry class I and class II mutations.
such as GATA1, and also the presence of additional copies of genes
on chromosome 21 that facilitate leukemogenesis, such as the onco-
genes RUNX1, ERG, and ETS2. Chromosomal Abnormalities

Mendelian Acute Myeloid Leukemia The central role of acquired mutations in AML was first recognized
through the identification of recurrent nonrandom cytogenetic altera-
Predisposition Syndromes tions in the mid-20th century. Recurrent karyotypic lesions are frequent
events in AML, present in roughly 50% to 60% of patients at diagnosis,
A number of genes that are targets of recurrent somatic mutation in and have distinct prognostic significance that are central to treatment
AML are also mutated in the germline in families with predisposition decisions, including the identification of patients for whom hemato-
to myeloid malignancy without a prodrome of bone marrow failure. poietic cell transplantation should be considered in first remission, as
These include mutations in RUNX1, CEBPA, and GATA2. Predispo- well as patients likely to achieve a favorable outcome with chemo-
sition to AML is also associated with germline variants in ANKRD26, therapy alone (Fig. 58.1). Common chromosomal abnormalities
SRP72, ETV6, and DDX41. Although these familial syndromes are include chromosome translocations or inversions, chromosome dele-
rare, they are important to recognize, since affected individuals and tions, and monosomies or trisomies. Patients can be stratified according
asymptomatic carriers require specific clinical management. to karyotype into favorable, intermediate, and poor-risk categories.
Familial platelet disorder with predisposition to acute myelogenous Typically, favorable risk includes patients with t(15;17), t(8;21) or
leukemia (OMIM 601399) is associated with autosomal dominant inv(16)/t(16;16), and adverse risk includes inv(3q)/t(3;3), t(6;9),
inheritance of germline mutations in RUNX1. Mutation carriers monosomy 7, monosomy 5, loss of 5q, 7q, or 17p, and complex
frequently present with easy bruising/bleeding due to quantitative or (greater than 3) chromosomal abnormalities, as well as most transloca-
qualitative platelet dysfunction and have an approximately 40% tions involving the MLL locus on chromosome 11q23. In lieu of
lifetime risk of developing AML, typically in the third or fourth additional molecular studies, all other karyotypic lesions are generally
decade. classified as intermediate risk. This includes patients with a normal
Germline mutations in the CEBPA gene are a rare cause of karyotype, which comprise approximately 45% of all AML cases.
autosomal dominant familial predisposition to AML (OMIM
116897). The germline mutations are typically truncating at the
N-terminus of the protein, with acquisition of a C-terminal somatic Retinoic Acid Receptor Rearrangements
mutation as a common event in the development of AML among
these patients. These cases have a relatively favorable prognosis, A distinct subset of AML, acute promyelocytic leukemia (APL) or
similar to de novo AML with somatically-acquired biallelic CEBPA FAB M3, comprises approximately 10% of adult AML cases, and is
mutations. defined by the presence of a translocation involving the retinoic acid