Page 137 - Hematology_ Basic Principles and Practice ( PDFDrive )

108 Part II Cellular Basis of Hematology

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mice. Conversely, activation of PLG by administration of tissue cells secrete Angiopoietin 1 (ANGPT1) and that deletion of Angpt1
plasminogen activator promoted HPC proliferation and differentia- in these cell populations accelerated vascular and hematopoietic
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tion after myelosuppression, and this effect was dependent on matrix recovery in mice after irradiation. Taken together, these studies
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metallopeptidase 9–mediated release of c-Kit ligand. Similarly, reveal the remarkable complexity and orchestration of molecular
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Trowbridge et al reported that mice that were heterozygous for the responses to myelotoxicity and also suggest several potential pathways
hedgehog receptor Ptc1, displayed earlier recovery of hematopoiesis that can potentially be exploited for the therapeutic regeneration
after 5-FU-induced myelosuppression compared with wild-type lit- of HSCs.
termate mice. Hedgehog binding blocks PTC1-mediated inhibition Lastly, the effect of age on the capacity for HSCs to regenerate
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of SMO, thereby promoting downstream Hedgehog signaling. There- after myelosuppressive challenge remains an important question.
fore, heterozygous Ptc1 mice have enhanced Hedgehog signaling, and Clinical studies have confirmed the impaired reconstitutive capacity
these results implicate Hedgehog signaling as positively regulating of HSCs from older patients in autologous stem cell transplant set-
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short-term hematopoietic regeneration after injury. However, this tings. Not surprisingly, older mice with defects in DNA damage
acceleration in hematopoietic recovery in mice heterozygous for repair mechanisms (nucleotide excision repair, nonhomologous
Ptc1 occurred at the expense of LT-HSCs, which were exhausted in end-joining) and telomere maintenance displayed severe defects in
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these mice. Genetic studies have similarly demonstrated that the their capacity to reconstitute hematopoiesis after transplantation
homozygous deletion of Ship in mice (SH2-containing inositol phos- into lethally irradiated recipient mice compared with age-matched
phatase) is associated with increased loss of HSCs after 5-FU exposure control subjects that retained the DNA repair and telomerase
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compared with heterozygous Ship deletion. In a similar model of genes. Furthermore, Flach et al recently showed that aging HSCs
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5-FU-mediated myelosuppression, Nemeth et al reported that mice display heightened levels of replication stress during cell cycling as
deficient in the high-mobility group box 3 (Hmg3b) DNA binding a result of decreased expression of mini-chromosome maintenance
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protein exhibited more rapid recovery of phenotypic HSCs compared replicative helicase components and altered DNA replication forks.
with wild-type mice. The enhanced recovery of the stem/progenitor Therefore, therapeutic targeting to accentuate these DNA repair and
pool in Hmgb3-deficient mice was associated with activation of WNT replication mechanisms may facilitate the recovery of the functional
signaling, again suggesting that activation of the WNT pathway may HSC pool after myelosuppression and may lessen the oncogenic risk
accelerate HSC recovery after myelosuppression. Of note, expression incurred via repeated exposure to DNA-damaging therapies (e.g.,
of a constitutively active form of the signal transducer and activa- alkylators and irradiation). 512,513 Interestingly, prolonged fasting has
tor of transcription 3 (Stat3) in HSCs increases their regenerative been shown to ameliorate chemotherapy-induced HSC damage
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capacity after transplant into lethally irradiated mice. In this and age-dependent myeloid bias in mice, associated with reduc-
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study, it was not determined whether alteration in Stat3 expression tion in IGF1 levels. Further research into the HSC-autonomous
affected HSC regeneration after myelosuppression (e.g., 5-FU or and extrinsic mechanisms which regulate HSC aging and HSC
irradiation). 497 regeneration during aging should be prioritized going forward and
At the cellular level, increasing evidence suggests an important will hopefully yield therapeutic avenues to reverse some aspects of
role for BM ECs in promoting hematopoietic regeneration after hematopoietic aging.
myelotoxic stress. 498–501 Genetic deletion or antibody-based inhibition
of VEGFR2, which is expressed by sinusoidal BM ECs, was shown to
delay both BM vascular and hematopoietic recovery after total-body HEMATOPOIETIC STEM CELLS AND MALIGNANCY
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irradiation (TBI). Systemic infusion of syngeneic or allogeneic ECs
has also been shown to significantly accelerate the recovery of both Similar to the HSC at the apex of the hematopoietic hierarchy, an
the HSC pool and overall hematopoiesis in mice after high-dose entity termed a leukemic stem cell (LSC) has been proposed to drive
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TBI. 501,502 Salter et al and Butler et al further demonstrated tumorigenesis because of its ability to self-renew and reinitiate leuke-
that hematopoietic regeneration after irradiation is dependent on mia upon transplantation in an experimental setting (e.g., mouse
VE-cadherin-mediated vascular reorganization because administra- transplant; Fig. 9.4). 515–517 A clonal origin of a hematopoietic malig-
tion of a neutralizing anti-VE-cadherin antibody caused significant nancy was first demonstrated for CML where the presence of the
delay in hematologic recovery in mice after TBI. While the precise characteristic Philadelphia chromosome in myeloid, erythroid,
mechanisms through which BM ECs regulate HSC regeneration megakaryocytic and B-lymphoid cells suggested a common origin, 518–
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in vivo remain unclear, it was shown that systemic administration 520 which was later proven by molecular analysis. Genetic analyses
of PTN, a heparin binding growth factor that is secreted by both in a case of CML also provided the first proof for another important
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BM and brain ECs, causes a rapid increase in recovery of the HSC concept in cancer, that of clonal evolution (see Fig. 9.4), which
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pool in mice after high-dose TBI. Taken together, these studies had already been hypothesized for solid tumors. This model posits
suggested that the BM vascular niche may be an important reservoir that a subclone within the initial LSC-derived clone acquires addi-
for the discovery of growth factors and membrane-bound proteins tional genetic or epigenetic alterations that convey a growth advantage
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that mediate HSC regeneration. Additional studies have further and lead to heterogeneity within the tumor. Whereas the HSC pool
validated the important role of the BM vascular niche in regulating itself does not expand during progression of chronic phase CML to
HSC regeneration following myelosuppressive injury. Deletion of blast crisis, granulocyte-macrophage progenitors (GMPs) with
the proapoptotic proteins, BAK and BAX, from Tie2-expressing BM increased expression of the continuously active tyrosine kinase fusion
ECs was shown to protect HSCs from radiation-induced depletion protein BCR-ABL and high self-renewal capacity driven by activation
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in mice, independent of HSC-autonomous effects. Furthermore, of nuclear β-catenin are amplified. Thus, the LSC may differ from
Doan et al reported that EGF is expressed by BM ECs after TBI the tumor-initiating “cell of origin”. 161,523 While in CML the tumor-
and that systemic administration of EGF improved HSC regenera- initiating HSC maintains the chronic phase of the disease, subsequent
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tion and survival after TBI. EC-specific deletion of the NOTCH genetic events arising in the GMPs give rise to LSCs sustaining the
ligand, Jagged1, has also been shown to cause delayed white blood blast crisis.
cell recovery and decreased survival in mice following sublethal The first cancer stem cell to be identified in any malignancy was
+
+
−
+
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TBI. Interestingly, recent studies have suggested several novel the LSC in AML. 517,524 CD34 CD38 cells but not CD34 CD38 cells
mechanisms through which HSC regeneration can be augmented derived from all known AML subtypes (except for the AML subtype
following radiation-induced myelotoxicity, including augmentation M3) repopulated secondary NOD/SCID recipient mice and fully repro-
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of the thrombomodulin-activated protein C pathway, administra- duced AML. 524,525 Next-generation sequencing efforts have revealed the
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tion of the bactericidal/permeability-increasing protein (rBPI 21), clonal evolution in primary and relapsed AML. 287,334,345,526–529 While
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activation of nuclear factor erythroid-2-related factor 2 or Ras/ healthy and AML genomes contain hundreds of exonic mutations,
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MEK/ERK signaling in HSCs. Interestingly, it was also recently as few as two key somatic “driver” mutations enable clonal expansion
shown that both HSCs and leptin receptor-expressing BM stromal of a cell that takes along all the background “passenger” mutations.