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Chapter 62 Acute Myeloid Leukemia in Children 983

MLL-MLLT4
1%
CBFβ-MYH11 MLL-MLLT10
10% 1%
MLL-ABI1
1%
MLL-MLLT3 8%

RUNX1-RUNX1T1 15%

DEK-NUP214
1%
Other MLL
9% MYST3-CREBBP
1%
RUNX1-CBFA2T3
1%
CBFA2T3-GLIS2
1%
RBM15-MKL1
1%
CEBPA
5% −7
1%
Other 9%

NPM1-mut/FLT3-ITD
TET2 3%
5%
NPM1- mut/FLT3-wt
4%
FLT3-TKD
5%
NPM1-wt/FLT3-ITD 8%
IDH1/IDH2
3%
WT1 8%
Fig. 62.1 FREQUENCIES OF RECURRENT GENETIC LESIONS IN CHILDHOOD ACUTE
MYELOID LEUKEMIA. MLL, Mixed lineage leukemia.

fusion protein retains the high-affinity binding domain, further sug- contribution of MLL-deficient embryonic stem cells in chimeric
gesting that dominant repression of RUNX1 is not the only mecha- animals found an absence of lymphoid and myeloid populations
nism through which the fusion gene contributes to leukemogenesis. derived from the MLL-deficient stem cells, demonstrating a require-
The targets of the RUNX1-independent mechanism are unknown, ment for MLL in either the specification or expansion of HSCs
as are the relative importance of the dependent and independent during development. Conditional knockout of the Mll gene in adult
activities. mice leads to bone marrow failure within 3 weeks, providing evidence
that MLL is not only required for definitive hematopoiesis, but is
also required for maintenance of HSCs in postnatal hematopoiesis.
MLL Gene Rearrangements Chromosomal translocations involving the MLL gene are associ-
ated with both AML and ALL leukemias, with more than 50 different
The MLL gene, located on chromosome 11 band q23, is a mam- translocation partners identified. MLL rearrangements are found in
malian homologue of the Drosophila trithorax (Trx) protein. The 60%–70% of infants with leukemia, regardless of immunophenotype,
trithorax protein in Drosophila positively regulates homeodomain but are less common in older children and adults. The distribution of
(HOX) genes, a set of transcription factors that specify cell identity translocation partners varies depending on the age of the patient and
along the anteroposterior axis of segmented animals during embry- the immunophenotype of leukemia, with MLLT3, MLLT10, MLLT4,
onic development. Their positive regulation is countered by and ELL being more frequent in pediatric AML. With the exception
Polycomb-group (PcG) proteins, such as BMI1, which act as tran- of internal partial tandem duplications (PTD) of MLL (MLL-PTD),
scriptional repressors of the HOX genes. the majority of MLL rearrangements contain the N-terminus of MLL
MLL encodes a protein of approximately 500 kDa with multiple and the C-terminus of the fusion partner gene. Some of the partner
domains that form part of a multiprotein complex involving tran- genes are nuclear proteins with transcription modulation activity
scription regulators including TFIID, SWI/SNF, NuRD, hSNFsH, that lead to activation of MLL target loci, while others are either
and SIN3A. This complex is responsible for chromatin remodeling, cytoplasmic or membrane bound with diverse functions but share
including acetylation, deacetylation, and methylation of nucleosome- in common the presence of dimerization/oligomerization domains.
attached histones. MLL is thought to play a role in the recruitment Oligomerization promotes enhanced recruitment of transcription
of proteins, assembly of the complex, and is required for transcrip- cofactors as well as stabilization of the large multiprotein transcrip-
tional elongation of its target genes. Experiments evaluating the tional complex.