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Chapter 9 Hematopoietic Stem Cell Biology 103

Transcription Factors Required for the Specification mutations in RUNX1 are observed in patients with various hemato-
logic diseases including MDS, CMML, ALL, de novo and therapy-
of HSCs related AML and the autosomal dominant preleukemic syndrome
familial platelet disorder with predisposition to AML (FPD/AML). 288
As one of the few transcription factors known to be essential for the
mesoderm-hemangioblast transition, the ETS class protein ETV2 is
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expressed in a subset of FLK1 cells with enhanced endothelial and Transcription Factors Required for HSC
hematopoietic potential and downregulated thereafter. 246,247 Together Homeostasis
with the forkhead transcription factor FOXC2, it cooperatively
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induces the FLK1 mesoderm by stimulating the expression of key Many transcription factors from different protein classes that play a
endothelial and hematopoietic genes such as Flk1, vascular endothelial role in setting up the hematopoietic hierarchy are necessary for HSC
1
(VE)-cadherin, Tie2, Scl and Notch4. 248 self-renewal in competitive transplantation assays. For example, SCL
Before the emergence of HSCs, the bHLH protein SCL is required is expressed much higher in LT-HSCs compared to ST-HSCs, and
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for the specification of the bipotent hemogenic endothelium within promotes their quiescence, which preserves the LT-HSC pool.
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the hemangioblast during embryonic development. Its knockout In HSCs as well as differentiating progenitors, SCL exists in different
in mice, as well as that of its binding partner LIM domain protein complexes most of which include GATA2 (or GATA1 in the erythroid
Lmo2, 250–252 results in the lack of hematopoiesis with early embryonic lineage), E2A and the non-DNA binding adaptor proteins LMO2
lethality, 253–256 and an absence of adult HSCs. 257,258 SCL expression is and LDB1. 279,291 Loss of any of these SCL partners leads to defects
regulated by three hematopoiesis-specific enhancers, one of which in HSC maintenance. 255,262,292–294 Apart from GATA2 and LMO2,
comprises an ETS/ETS/GATA motif that binds ETS transcription also deregulation of E2A causes hematologic malignancies. Six
factors FLI1 and ELF1 as well as GATA2, revealing the transcriptional percent of all pediatric ALLs, in particular pre-B cell ALL (23%) are
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cascade at the top of the hematopoietic hierarchy. Interestingly, caused by a chromosomal translocation that fuses the E2A gene with
once emerged, HSCs require either SCL or the closely related bHLH PBX1 (pre-B-cell leukemia homeobox 1), 295,296 which encodes an
factor LYL1 for function and survival. 260–262 Elevated expression of important HOX interacting factor discussed later.
SCL and/or LMO2, as well as LYL1 is found in 35–65% of T-cell The ETS-related transcriptional repressor TEL/ETV6 is specifi-
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acute lymphoblastic leukemia (T-ALL), mostly because of chromo- cally required for HSC survival but not their emergence. Like E2A,
some translocations but also, in the case of SCL, intragenic also ETV6 is involved in chromosomal translocations; the ETV6-
deletions. 263 RUNX1 is the most common fusion gene in pediatric cancers, found
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GATA2, a zinc finger transcription factor, is expressed before HSC in 22% of childhood ALL (of the pre-B-cell subtype). In contrast
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emergence in the paraaortic splanchnopleura and later in the AGM. to the translocation generating the E2A-PBX1 fusion gene most of
GATA2 has been shown to be essential for the production of cells the ETV6-RUNX1 fusions seem to originate in utero. 299
belonging to all lineages in definitive (or adult) hematopoiesis. 265,266 Another transcription factor associated with human malignancies,
Interestingly, it functions to preserve the pool of immature HSPCs EVI1, is specifically expressed in LT-HSCs. When overexpressed in
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by preventing the differentiation of hematogenic precursor cells. mice Evi1 boosts LT-HSC self-renewal, whereas its heterozygous loss
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Thus, reduction of GATA2 expression or activity is a prerequisite for leads to marked reduction of their self-renewal capacity. Aberrant
HSC commitment. Heterozygous germline mutations in GATA2 are expression of EVI1 isoforms is observed in 8–11% of AML, 301,302 and
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the cause of several previously known clinical syndromes: MonoMAC 28% of mixed-lineage leukemia (MLL)-rearranged AML, and
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(monocytopenia and Mycobacterium avium complex infections), 268,269 usually associated with a poor prognosis. Furthermore, its translo-
which are also described as combined dendritic cell, monocyte, B and cation with ETV6 or RUNX1 is associated with progression to blast
natural killer lymphoid or DCML deficiency. 270,271 Individuals with crisis in chronic myeloid leukemia (CML). 304,305
MonoMac almost invariably progress to a distinct form of myelodys-
plastic syndrome (MDS) and in 14% and 8% to acute myeloid
leukemia (AML) and chronic myelomonocytic leukemia (CMML), The HOX Cluster in HSC Self-Renewal
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respectively. Familial myelodysplastic and AML syndrome as well
as Emberger syndrome (primary lymphedema with predisposition to Homeobox (HOX) genes encode homeodomain-containing tran-
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AML) also belong to this group, and in some cases are caused by scription factors critical for embryonic patterning, organized into
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the identical GATA2 mutation. four paralogous clusters (A, B, C, and D) on four chromosomes.
The core-binding protein RUNX1 and its obligate binding partner Because of limited DNA sequence specificity and selectivity, HOX
CBF-β are both required for the transition from hemogenic endo- proteins function through interaction with DNA-binding cofactors,
thelium to definitive HSCs. 275–278 Runx1 expression is upregulated in particular, PBX and/or myeloid ectopic insertion site (MEIS)
during the endothelial-to-hematopoietic transition (EHT) in the family members. 307,308 At least 22 of the 52 HOX genes (none from
hemogenic endothelium, probably by GATA2, the ETS transcription the HOXD cluster) are expressed in mouse and human HSPCs and
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factors FLI1 and PU.1 and the SCL complex (SCL, LMO2, LDB1). are subsequently downregulated to permit lineage commitment.
RUNX1 then induces expression of other critical transcription factors Therefore, continuous HOX expression generally blocks differentia-
such as GFI1 and GFIB which in turn downregulate the endothelial tion and leads to rapid expansion of preleukemic HSPCs. In mice,
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markers TIE2, VE-cadherin and KIT. In addition, RUNX1 causes overexpression of HOXA10 has been shown to block myeloid and
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rapid global reorganization of transcription factors such as SCL, FLI1 lymphoid differentiation leading to AML. This is also the case for
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and C/EBPβ which is critical for the EHT and hematopoietic fate. Hoxa9, in particular conjunction with Meis1 or the E2A-Pbx1 fusion
RUNX1 is also required to antagonize the effects of the homeobox gene. 311–313 HOXA9 overexpression belongs to a gene signature that
transcription factor HOXA3, a negative regulator of specification of distinguishes AML from ALL, and in AML patients highly correlates
the hemogenic endothelium. HOXA3 represses a cascade of transcrip- with treatment failure. 314
tion factors that promote hemogenesis while at the same time inducing A number of leukemic chromosomal translocations, either directly
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a set of genes critical for maintaining endothelial character. RUNX1 or indirectly, lead to the overexpression of HOX genes. The nuclear
and CBF-β are the most common target of chromosomal transloca- pore complex protein NUP98 was first implicated in hematologic
tions in acute leukemia. In particular, translocations resulting in malignancies by the discovery of NUP98-HOXA9 fusions in
RUNX1-ETO and CBF-β-MYH11 cumulatively account for 15% of AML. 315,316 Approximately half of all NUP98 translocations involve
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AML. Consistent with the fact that neither RUNX1-ETO nor HOX genes, most commonly HOXA9 in AML, MDS, CML and
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CBF-β-MYH1 induce leukemia by themselves in mouse models CMML, but also HOXA11 and HOXA13 as well as their paralogues
but rather require additional mutations, next-generation sequencing in the B and C cluster. 317,318 While the overall prevalence of these
studies have identified both as preleukemic lesions. 286,287 In addition, fusions is low, they are associated with a poor prognosis. 319