Page 1116 - Hematology_ Basic Principles and Practice ( PDFDrive )

982 Part VII Hematologic Malignancies

of the molecular pathology of pediatric AML. Ongoing DNA
Allogeneic Hematopoietic Stem Cell Transplantation in
BOX 62.1 First Remission sequencing efforts and studies on the epigenetic state of leukemia
cells, coupled with biologic studies to understand the role of indi-
Although the use of allogeneic hematopoietic stem cell transplantation vidual mutations as well as the spectrum of mutations within a given
(HSCT) in first remission is controversial, we recommend it for high-risk patient, will likely produce a much deeper understanding of the
patients, including those with -7, t(6;11)(q27;q23), t(10;11)(p12;q23), disease and mechanisms of drug resistance over the next several years.
t(10;11)(p11.2;q23), t(5;11)(q35;p15.5), t(6;9)(p23;q34), t(8;16) In this chapter we discuss the major subtypes of AML and our current
(p11;p13), inv(16)(p13.3q24.3), and t(16;21)(q24;q22). Until the understanding of the biologic processes that mediate disease.
impact of FLT3 inhibitors on the outcome of patients with FLT3 internal
tandem duplication (ITD) has been determined, we recommend HSCT
for patients with FLT3-ITD and high allelic ratios or poor response to The Core-Binding Factor Leukemias
therapy. Patients who do not have high-risk genetic features but who
have high (>1% after the first course of therapy) or persistent (>0.1%
after two courses of therapy) levels of minimal residual disease (MRD) The CBF transcription complex is a heterodimeric complex com-
are also at high risk of relapse and are therefore candidates for HSCT posed of an alpha DNA-binding subunit (RUNX1, RUNX2, or
in first remission. Because recent studies have demonstrated that RUNX3), and a non-DNA-binding beta subunit (CBFβ). The
outcomes after HSCT are similar regardless of donor type, we believe complex functions as a master regulator that controls the birth of the
that the decision to perform HSCT in first remission should be based definitive hematopoietic stem cell (HSC) during embryogenesis and
on the factors described above, rather than on the availability of a plays important roles in normal hematopoietic cells, both in the
matched donor. Thus, patients who are classified as high-risk acute control of their differentiation state as well as their effector functions.
myeloid leukemia based on genetic features or MRD should undergo RUNX1 was the first identified mammalian CBF gene and was iso-
HSCT using a matched sibling donor, matched unrelated donor,
haploidentical donor, or cord blood in first remission. Prior to transplant, lated as part of the AML-associated translocation t(8;21)(q22;q22.3).
reasonable efforts should be made to reduce the level of MRD as much Following the discovery of RUNX1, the inv(16) and the less common
as possible without causing organ toxicity or infectious complications t(16;16)(p13;q22), which are found in the majority of acute mono-
that may increase transplant-related morbidity or mortality. blastic leukemias with eosinophilia (FAB-M4Eo), were cloned and
shown to result in a fusion between CBFβ and MYH11, the gene
that encodes smooth muscle myosin heavy chain (SMMHC). Subse-
quently, rare somatic mutations of RUNX1 were detected in de novo
TABLE 2016 World Health Organization Classification of AML, with the highest frequency (40%) seen in the FAB-M0 subtype.
62.1 Acute Myeloid Leukemia and Related Neoplasms These mutations lead to impairment in DNA binding or decreased
Acute myeloid leukemia with recurrent genetic abnormalities transcriptional activity. Collectively, these data reveal that mutations
AML with t(8;21)(q22;q22); RUNX1-RUNX1T1 in the genes encoding the RUNX1/CBFβ transcription factor
AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB- complex are one of the most common lesions seen in de novo AML,
MYH11 occurring in approximately 25% of cases.
APL with t(15;17)(q22;q12); PML-RARA The most frequently observed rearrangement in AML is the
AML with t(9;11)(p22;q23); MLL-MLLT3 t(8;21), which fuses the 5′ portion of RUNX1 to almost the entire
AML with t(6;9)(p23;q34); DEK-NUP214 coding region of RUNX1T1. The RUNX1-RUNX1T1 fusion product
AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1 functions primarily as a transcriptional repressor, inhibiting the
AML (megakaryoblastic) with t(1;22)(p13;q13); RBM15-MKL1 expression of lineage-specific genes that are normally activated by the
AML with mutated NPM1 RUNX1-CBFβ complex to promote myeloid differentiation. In
AML with mutated CEBPA human and murine systems, expression of RUNX1-RUNX1T1 is
Provisional entity: AML with BCR-ABL1 insufficient to induce leukemia, but does establish a preleukemic
Provisional entity: AML with mutated RUNX1 population that has enhanced self-renewal properties and can acquire
Acute myeloid leukemia with myelodysplasia-related changes additional mutations over time to lead to overt leukemia. Consistent
Therapy-related myeloid neoplasms with this hypothesis, in bone marrow samples from patients that have
Acute myeloid leukemia, not otherwise specified achieved a clinical remission, rare progenitors expressing RUNX1-
AML with minimal differentiation RUNX1T1 are present and can persist for years without expanding.
AML without maturation These cells also retain the ability to differentiate into multiple lin-
AML with maturation eages, so arguably they are not fully leukemic in nature. Cooperating
Acute myelomonocytic leukemia mutations that promote full transformation identified in patients
Acute monoblastic/monocytic leukemia with CBF alterations include FLT3, c-KIT, and RAS among others,
Pure erythroid leukemia many of which confer a proliferative advantage.
Acute megakaryoblastic leukemia The inv(16)/t(16;16)-encoded CBFβ-MYH11 fusion protein
Acute basophilic leukemia retains the RUNX1 binding domain and therefore its ability to
Acute panmyelosis with myelofibrosis interact with wild-type RUNX1. This chimeric protein functions in
Myeloid sarcoma a dominant manner to inhibit normal RUNX transcriptional activity.
Myeloid proliferations related to Down syndrome Interestingly, 90% of CBFβ-MYH11 conditional knock-in mice
Transient abnormal myelopoiesis spontaneously developed AML with a latency of 5 months, implying
Myeloid leukemia associated with Down syndrome that fewer cooperating mutations are necessary for this chimeric
oncogene than RUNX1-RUNX1T1. These results may be explained
AML, Acute myeloid leukemia.
Modified from Arber DA, Orazi A, Hasserjian R, et al: The 2016 revision to the by increasing evidence that CBFβ-MYH11 has functions indepen-
World Health Organization classification of myeloid neoplasms and acute dent of RUNX1 repression. Knock-in mice expressing a mutant
leukemia, Blood 127:2391, 2016 Cbfβ-MYH11 allele that has low binding affinity for Runx1 demon-
strate decreased repression of Runx1, but this did not correlate with
reduced leukemogenesis. In fact, the mice developed leukemia faster,
different subclones may have different growth characteristics and suggesting that there are Runx1-independent mechanisms of trans-
drug sensitivities depending on the complement of mutations present. formation by the chimeric protein. An analogous setting occurs in
However, the most robust AML clones in the laboratory, as deter- patients as well, whereby a small percentage of inv(16) AML patients
mined by engraftment into immunodeficient mice, do not necessarily produce a fusion protein that lacks the high-affinity binding domain
equate to the dominant clone at diagnosis nor the clone that leads to responsible for enhanced binding to RUNX1. The clinical course and
relapse. It is thus clear that we still have an incomplete understanding characteristics of these cases do not differ from cases in which the