Page 1031 - Hematology_ Basic Principles and Practice ( PDFDrive )

914 Part VII Hematologic Malignancies

Exposure to ionizing radiation also has been identified as a caus- Epigenetic modifications of the MDS genome appear to also play a
ative mechanism for tAML. This relationship was identified in the significant role in AML progression, particularly through DNA
context of occupational exposures during the development of radiog- methylation-mediated silencing of tumor suppressor genes.
raphy, and subsequently in the setting of mass exposures such as the
atomic bomb detonations or nuclear power plant disasters, where a
time-limited spike in leukemia incidence occurred following the Congenital Bone Marrow Failure Syndromes
event. Outside of these events, therapeutic radiation therapy repre-
sents the most common setting for significant radiation exposure, A number of inherited bone marrow failure syndromes are associated
which is associated with a small but significant increase in tAML risk. with an increased risk of developing advanced myeloid malignancies.
Radiation-associated tAML is characterized by an increased frequency This may be due to the proliferative stress imposed by chronic
of mutations otherwise implicated in de novo AML pathogenesis— cytopenias or defects in DNA repair that are hallmarks of several of
for instance, mutations in RUNX1, as well as balanced translocations these syndromes.
such as RUNX1-RUNX1T1 and DEK-NUP214—suggesting some Fanconi anemia (FA) is the most common inherited bone marrow
selectivity in the patterns of DNA damage. failure disorder, and is caused by germline mutations in factors
involved in DNA repair. These disorders have an autosomal recessive
inheritance pattern except for FANCB, which is X-linked. To date,
Prior Hematologic Malignancy 17 genes have been identified as a part of the FANC gene family, and
together their protein products are responsible for identifying DNA
Other myeloid malignancies, including myelodysplastic syndromes damage and targeting these sites for repair. The FA core complex is
(MDS) and myeloproliferative neoplasms (MPNs), carry a risk of recruited to the site of DNA damage after exposure to crosslinking
disease evolution to sAML. The risk varies depending upon the agents. FANCD2 is ubiquitinated by the core complex, and forms
underlying disease, and may be facilitated by certain exposures, the link between the FA and BRCA DNA repair pathways. Pheno-
including genotoxic chemotherapy. typically, patients with FA have short stature, abnormalities of the
Patients with MPNs have an approximately 10% risk of evolution thumb and radius, skin findings including hyperpigmentation and
to AML over 10 years, which varies according to the underlying café au lait spots, microphthalmia, endocrinopathies, and often
disease. The risk is lowest in essential thrombocythemia and as present with aplastic anemia later in childhood. The cumulative risk
high as 20% for myelofibrosis. There is a clear association between of AML or MDS among FA patients is approximately 10% to 15%,
therapies used in treating MPNs, specifically alkylating agents and with peak incidence during the teenage years.
radioactive phosphorus, and AML evolution; treatment with these Dyskeratosis congenita (DKC) is a bone marrow failure syndrome
agents results in a three to fourfold increase in incident AML. characterized by inherited mutations in the telomere maintenance
Another mechanism that may contribute to clonal evolution and pathway. DKC can be inherited in an autosomal dominant (Online
disease progression may be a chronic inflammatory state related Mendelian Inheritance in Man [OMIM] 127550), autosomal reces-
to the underlying MPN. Sequencing of sAML cases developing in sive (OMIM 224230), or X-linked recessive pattern (OMIM
the background of an MPN has identified recurrent mutations in 305000). Mutations in TERT, DKC1, TERC, or TINF2 account for
TET2, JAK2, IDH, IKZF1, and ASXL1. Moreover, a number of most cases. Typical findings among patients with DKC include the
patients with a JAK2 mutated MPN may develop JAK2 wild-type “triad” of skin hyperpigmentation, nail dystrophy, and oral leukopla-
AML, thought to arise either from a common pre-JAK2 founding kia, and these patients will typically develop bone marrow failure by
clone, or due to parallel expansion of a distinct hematopoietic clone. 20–30 years of age. As a result of the underlying mutation, patients
Post-MPN AML with mutated JAK2 typically proceeds through have markedly shortened telomeres, which contribute to bone
an accelerated myelofibrosis phase, while post-MPN AML that marrow failure, as well as damage to other organs including pulmo-
no longer harbors a JAK2 mutation tends to arise from chronic nary fibrosis and hepatic cirrhosis. Transformation to AML occurs in
phase disease and may be associated with the use of cytotoxic approximately 10% of patients, and is thought to occur via genomic
therapies. instability related to shortened telomeres and associated DNA
Prior to the introduction of tyrosine kinase inhibitors (TKIs) for damage, resulting in dysplasia and an increased risk of hematopoietic
CML, patients with CML typically progressed from chronic phase to malignancy.
blast phase within 5 years, at a rate of over 20% per year. Most cases Shwachman–Diamond syndrome (OMIM 260400) is an autoso-
of blast phase CML have a myeloid phenotype, while approximately mal recessive disorder caused by mutations in SBDS. Hematopoietic
30% of patients have a lymphoid phenotype. Additional mutations manifestations of Shwachman–Diamond syndrome most often
may occur during transformation of CML, and approximately 80% of include isolated neutropenia, although many patients will eventually
patients have additional cytogenetic abnormalities, such as duplication develop pancytopenia, which may progress to aplastic anemia. AML
of the Philadelphia chromosome, and other trisomies that are recurrent or MDS occurs in up to a third of patients by 30 years of age, and
in de novo AML. Up to one-third of patients with CML in myeloid is thought to relate to chromosomal instability and accelerated rates
blast phase harbor mutations in the tumor suppressor genes P16 or of apoptosis, which may be due to the role of SBDS in stabilizing the
TP53. Additionally, BCR-ABL signaling upregulates transcription mitotic spindle during mitosis.
factors implicated in AML pathogenesis, including HOXA9 and EVI1, Severe congenital neutropenia or Kostmann syndrome is associ-
which may contribute to leukemic transformation. Underscoring the ated with neutropenia at birth and has been associated with a variety
continued requirement for BCR-ABL1 signaling in CML evolution, of genetic mutations. The pattern of inheritance can be autosomal
the rate of transformation to blast phase CML in the TKI era has dominant (ELANE or GFI1), autosomal recessive (HAX1, G6PC3,
decreased markedly to approximately 1% per year. VPS45, or JAGN1), or X-linked (WAS). The clinical course is marked
Approximately one third of patients with MDS progress to sAML, by bacterial infections from a young age; some patients may be
although this varies significantly according to the underlying MDS responsive to granulocyte colony-stimulating factor (G-CSF), but
subtype and disease characteristics, including the percentage of bone the rate of leukemic transformation is high among this group, with
marrow blasts, presence of characteristic cytogenetic abnormalities, nearly a third of patients developing AML or MDS within 10 years.
and cytopenias. Progression to leukemia is associated with acquisition Transformation into AML is frequently characterized by the acquisi-
of additional somatic mutations as well as epigenetic alterations tion of somatic mutations in CSF3R, which encodes the G-CSF
within the MDS clone. Mutations in transcription factors and receptor. The causal relationship to chronic G-CSF therapy remains
cytokine signaling genes, including RUNX1, NRAS, and ETV6, are controversial.
more common at progression to sAML, compared with the frequency Diamond–Blackfan anemia (DBA) (OMIM 105650) is character-
of these mutations at MDS diagnosis. Mutations in RUNX1 are ized by red cell aplasia and typically spares the leukocyte and platelet
enriched in populations with tAML and other forms of sAML. lineages. DBA is typically inherited in an autosomal dominant