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Chapter 9 Hematopoietic Stem Cell Biology 105

histone H2A ubiquitination. 378,379 EZH2 also recruits DNA methyl- regulated by MLL and highly induced in MLL-rearranged leukemias,
transferases to its target genes, thereby enhancing its repressive contributing to an unfavorable prognosis. 422,424 In this context,
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effect. Overexpression of Ezh2 in mice enhances LT-HSC self- miR-196 has been shown to be necessary for MLL-AF9 dependent
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renewal by silencing differentiation genes 381,382 and causing a shift to immortalization of BM cells. miRNAs can also function as tumor
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the expression of proliferation genes. EZH2 has been described suppressors, exerting their function by targeting oncogenes. For
with either tumor suppressive or oncogenic roles, depending on the example, the miRNA cluster miR-15a/miR16-1 is deleted or epige-
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cellular context. EZH2 gain-of-function mutations, resulting in netically silenced in 68% of chronic lymphoid leukemia patients,
overall “hyper-trimethylation”, occur in 7.2% and 21.7% of follicular resulting in the upregulation of its target oncogene BLC2. 426
lymphoma and diffuse large B-cell lymphoma, respectively. Loss-of- In contrast to miRNAs, little is known about the expression of
function mutations have been observed in 12% of myelodysplastic/ lncRNAs in HSPCs and only a few lncRNAs have been further
myeloproliferative neoplasms and 18% of T-ALL cases but are rare functionally characterized. Several recent studies have compiled lists
in de novo AML (1–2%). PRCs do not bind to DNA directly but of lncRNAs expressed in HSCs, some of which are downregulated in
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require the interaction with other proteins such as ASXL1. ASXL1 is more differentiated progeny 338,387 and in leukemic cells. Knock-
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mutated in 6–30% of AML and 43% of CMML. These mutations down of a lncRNA specifically expressed in mouse BM LT-HSCs
hinder ASXL1 from recruiting PRC2 to and thus repressing target increased self-renewal of HSCs in vivo and abolished recruitment of
genes such as HOXA9. 384 the transcription factor E2A, essential for the development of multi-
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lineage HPCs, to chromatin. HSCs from female mice depleted
for Xist lncRNA (responsible for X chromosome inactivation) were
Regulation of HSCs by Noncoding RNAs shown to have maturation defects and to be compromised in their
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repopulation capacity. Furthermore, all Xist mutant female mice
Sequencing the human genome revealed that less than 1.5% of the developed highly aggressive mixed myeloproliferative neoplasms/
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DNA encodes proteins but, remarkably, subsequent analyses dis- MDS. With those relatively few studies the overall relevance of
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covered that still 76% of the genome is transcribed into RNA. lncRNAs for the pathogenesis of hematopoietic diseases is not yet
Many noncoding RNAs (ncRNAs) are enriched in HSCs compared well understood.
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to hematopoietic progenitors. ncRNAs other than ribosomal RNAs
and transfer RNAs are arbitrarily categorized into long ncRNAs
(lncRNAs) and short ncRNAs if >200 or <200 nucleotides long, HEMATOPOIETIC STEM CELL METABOLISM
respectively. Among the short ncRNAs, microRNAs (miRNAs) are
~22-nucleotide regulatory ncRNAs that repress gene expression The role of oxidative and nonoxidative glucose metabolism in regu-
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predominantly by binding to the 3′ untranslated region of protein- lating HSC and HPC function has recently been elucidated. Wang
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encoding mRNAs leading to their destabilization. A miRNA can et al reported that deficiencies in either lactate dehydrogenase A
target large numbers of mRNAs, and a single mRNA can be regulated (LDHA) or the M2 isoform of pyruvate kinase (PKM2), two enzymes
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by multiple miRNAs. HSCs depend on miRNA function for their which catalyze the fermentation of glucose to lactate, result in dif-
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survival as demonstrated by the finding that deletion of Dicer or Ars2, ferential effects on HSC and progenitor cell function. Deletion of
both essential factors for miRNA biogenesis results in HSC apoptosis Ldha inhibited normal HSC and progenitor cell function, whereas
and BM failure. 390,391 More than 100 different miRNAs are specifi- deficiency in Pkm2 impaired progenitor cell function without affect-
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cally expressed during hematopoiesis, preferentially targeting and ing HSCs. The authors further showed that deficiency of either
fine-tuning expression of transcription factors and their upstream Ldha or Pkm2 inhibited leukemia initiation, suggesting that these
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activators. Hematologic malignancies show characteristic changes metabolic enzymes may be therapeutically useful in targeting leuke-
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in their miRNA expression profiles. For example, ALL samples can mia. Separately, Ito et al demonstrated that the loss of peroxisome
be classified into subtypes according to their miRNA expression proliferator-activated receptor δ (PPAR-δ) or inhibition of mitochon-
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patterns. 393 drial fatty acid oxidation induced the loss of HSC maintenance.
Numerous miRNAs are specifically enriched in HSPCs, including Interestingly, this PPAR-δ-FAO axis was considered to serve as a
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miR-155, miR-125a, miR-125b, 395–397 miR-29a, miR-126, “metabolic switch” which regulated HSC symmetric versus asym-
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and miR-130a. Overexpression of the miRNA cluster miR-99b/ metric division. The tumor suppressor gene, Lkb1, which encodes
let7e/125a or miR-125a alone is capable of expanding the HSC pool a serine/threonine kinase that regulates phosphorylation of AMP-
in mice, 391,395,400 potentially by inhibiting apoptosis of HSCs medi- activated protein kinase, was also shown to be essential for HSC
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ated by the proapoptotic gene Bak1, which is a miR-125a target. maintenance. Lkb1 inactivation was shown to deplete quiescent
In addition, several miRNAs have been implicated in regulating HPC HSCs associated with depletion of all hematopoietic subpopulations,
differentiation, including miR-155 (lymphoid and myeloid develop- coupled with mitochondrial defects, depletion of ATP and alterations
ment), 394,401 miR-223 (myeloid development) 402,403 and the miR-181/ in lipid and nucleotide metabolism. 432
miR-150/miR-17-92 cluster (lymphoid development). 404–407 The Not surprisingly, the metabolic state of HSCs is influenced by the
example of miR-155 shows that, like transcription factors, some hypoxic microenvironment in which HSCs reside. 433,434 Specifically,
miRNAs are repurposed during hematopoietic ontogeny. 408 hypoxia contributes to the maintenance of quiescent HSCs which
Most of the miRNAs conferring a competitive advantage to the have high expression of HIF-1α and rely primarily on anaerobic
engrafted BM have been implicated in malignant transformation, and glycolysis, rather than oxidative phosphorylation, to produce
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are therefore called oncomiRs. Overexpression of miR-125 family ATP. 434–436 The therapeutic importance of understanding the cellular
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members causes myeloid and lymphoid malignancies in metabolic state of HSCs was recently highlighted by Liu et al, who
mice 395,397,400,410,411 and they are upregulated in chromosomal translo- showed that treatment of HSCs with alexidine dihydrochloride,
cations leading to MDS/AML and B-cell ALL. 412–414 oncomiRs a selective inhibitor of the mitochondrial phosphatase PTPMT1,
contribute to leukemic phenotypes by different mechanisms such as reprogrammed HSC metabolism from aerobic to glycolysis, resulting
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expediting cell cycle transitions, targeting tumor suppressors such in increased HSC maintenance in culture. Alterations in HSC
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as TET2, or dysregulating the balance between lineage-specific metabolism have also been described with aging, thereby impacting
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transcription factors. miR-155, the first miRNA shown to be suf- HSC function. Mohrin et al recently reported that SIRT7, a histone
ficient to cause lymphoblastic leukemia or high-grade lymphoma in deacetylase which regulates the expression of the mitochondrial
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a transgenic mouse model, is overexpressed in B-cell lymphomas master regulator, nuclear respiratory factor 1, was reduced in aging
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and AML. 418,419 miR-196, which is upregulated specifically during HSCs. SIRT7 inactivation was shown to increase mitochondrial
the transition from quiescent LT-HSCs to ST-HSCs, targets several folding stress and compromise the regenerative capacity of HSCs,
of its neighboring HOX genes important for self-renewal such as suggesting that alterations in the mitochondrial unfolded protein
HOXA9. 408,420–423 Like HOX genes, miR-196b is transcriptionally response contribute to HSC aging. 438