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124 Part II Cellular Basis of Hematology

within it—either primary or induced by the presence of malignant with MDS and AML showed nuclear (activated) beta-catenin in
cell population—have been proposed to contribute toward tumor osteoblasts.
initiation, maintenance, and resistance to treatment. Here, we will Altogether, the above studies illustrate that perturbed BM micro-
summarize the data related to the role of microenvironment in the environment can act as a source of signals that promote malignant
pathogenesis of acute leukemia and myelodysplasia. For the review change in the hematopoietic compartment, and highlight their
of this topic in other hematologic neoplasms, readers are referred to potential role as therapeutic targets.
disease-specific chapters of this book.
Early in vitro studies alluded to significant contribution of
nonhematopoietic BM cells (collectively termed stroma) to the Niche Alterations by Leukemia
pathogenesis of acute leukemia. For example, fibroblastic stromal
cells from patients with AML were unable to support normal Just as the microenvironment can contribute to disordered hemato-
granulocytic-macrophage (GM) colony formation in contrast to poiesis, it can be disrupted and modified by leukemic cells leading
those obtained from normal individuals. However, when the stromal to competitive advantage over normal counterparts. Visualization of
cells were tested from patients in remission, they maintained growth BM niches by intravital microscopy studies revealed that primary
of GM colonies similar to normal stroma. Strikingly, when the ALL and AML blasts are able to downregulate CXCL12 expression
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patients relapsed, this GM colony-supporting ability was lost. In in the BM, causing the egress of normal CD34 HSPCs from the
another series of observations, when nonadherent cells from continu- BM and impairment of normal hematopoiesis. This process was
ous marrow cultures or GM-CSF–dependent progenitor cell lines mediated by the stem cell factor (SCF) secreted by leukemic blasts
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were cocultured with mouse stromal cells that had been previously and reversed upon SCF neutralization. Similarly, in myeloprolif-
irradiated, they developed factor-independence and multiple distinct erative disorders such as chronic myeloid leukemia (CML), it is
karyotypic abnormalities; upon subcutaneous injection, these newly thought that microenvironmental changes that are induced by
transformed cell lines produced granulocytic monomyeloid tumors malignant cells result in formation of self-reinforcing loop leading
that spread to spleen, lymph nodes, and BM. Although by no means to preferential expansion of leukemic cells at the expense of their
definitive, these studies suggested that either the altered stromal cells normal counterparts. Leukemia can also affect the niches indirectly,
may contribute to the emergence of leukemia, or leukemia itself may i.e., through perturbation of sympathetic innervation: both in
affect the nonhematopoietic compartment. Both of these hypotheses CML and AML, “sympathetic neuropathy” promotes leukemogen-
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found confirmation in the later studies reviewed later. esis through either reduction in quiescence-inducing nestin cells
or altering their differentiation properties and frequency relative
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to nestin-GFP high /NG2 cells. The “niche-modifying” ability
Niche Contribution to Leukemia Development of the leukemic cells in vivo is an area of ongoing investigation
because it suggests that the leukemic niche can be molecularly
The idea of “niche-induced oncogenesis,” or contribution of the distinct from the normal thus creating an opportunity for altering
microenvironment to the emergence of malignant disease, stems the leukemic niche as a means of reducing persistence of leukemia-
from the clinical observation of donor-induced leukemia. In this initiating cells.
condition, which has a reported incidence between 0.12% and
5%, the leukemic clone arises from an apparently normal donor
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hematopoietic cells after allogeneic BM transplantation. Although Therapeutic Targeting of Leukemic Niche
the etiology is clearly multifactorial, damage to the BM microenvi-
ronment, either because of previous chemotherapy or pretransplant The CXCR4–CXCL12 pathway is critical for homing and subsequent
conditioning, may be an important contributing factor. In keeping adhesion of not only normal, but also leukemic stem cells (LSCs) to
with this notion, several experimental mouse models illustrate that the BM microenvironment. Of note, the level of CXCR4 is elevated
microenviromental alterations, either alone or in conjunction with in patients with AML and is associated with a poor outcome. The
corresponding molecular lesions in the hematopoietic compart- presence of Flt3 internal tandem duplication (a poor prognostic
ment, can play a critical role in the initiation of malignant disease. factor in AML) is in turn associated with increased CXCR4 expres-
For example, the mice with deficiency of phosphatase and tensin sion. Experimentally, treatment of NOD/SCID mice transplanted
homologue (PTEN) both in the microenvironment and HSPC with primary human AML cells using a neutralizing antibody against
developed a myeloproliferative disorder, but PTEN deficiency in CXCR4 reduced the leukemic burden. Follow-up studies confirmed
HSPCs alone did not result in the disease. Similarly, widespread the antileukemic effect of blocking CXCL12–CXCR4 axis using
deletion of retinoblastoma protein or retinoic acid receptor led to competitive antagonists of CXCR4 (AMD3100 and AMD3254) in
the development of myeloproliferative disorder, in the latter case mouse models of AML. These findings formed the basis for ongoing
purely because of gene deletion in the microenvironment. Using a clinical trials of CXCR4 antagonist AMD3100 (Plerixafor) as a
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cell type-specific approach, it was found that targeted deletion of the chemosensitizing agent in AML. So far, these studies have confirmed
microRNA processing enzyme Dicer 1 in immature OLCs resulted safety and tolerability of this drug in combination with chemotherapy,
in development of myelodysplasia and acute leukemia associated but the effect on response rate and survival has not been
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with independent complex genetic changes. The effect of Dicer-1 demonstrated.
deletion was entirely attributable to the microenvironment because Another example of LSC niche dependence is a cell adhesion
transplantation of Dicer 1-deleted BM into normal microenviron- molecule CD44, which is present on the surface of leukemic cells
ment resulted in reversal of the myelodysplastic phenotype. Remark- and interacts with hyaluronan on the endosteal surface. Blocking the
ably, hematopoietic abnormalities were observed when Dicer-1 was interaction between CD44 and hyaluronan using activating CD4
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deleted in very immature OLCs (osterix ) but not in those at a more antibody had significant effect on LSC eradication and even cured
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mature differentiation stage (osteocalcin ). Deletion of Shwachman- some mice. The therapeutic effect of the antibody was more marked
Diamond-Bodian syndrome gene in immature OLCs recapitulated when it was administered soon after injection of human leukemic
the key features of the Dicer-1 deletion phenotype and implicated cells compared with the animals with established disease, suggesting
their role in its pathogenesis. In another striking example, niche that it acts predominantly at the stage when LSCs engage their
involvement in leukemia generation, mice carrying an OLC-specific respective niches. It is also possible that some of the effect of the
mutation of constitutively activated beta-catenin developed AML. CD44 antibody was attributable to differentiation induction in the
The leukemic process was microenvironment-dependent and medi- LSCs. Nevertheless, this study provided a proof-of-principle demon-
ated by Notch signaling. Genetic or pharmacologic inhibition of stration that LSCs interaction with the niche is required for their
Notch signaling lead to reversal of the leukemic phenotype. The survival and leukemia progression and thereby raised the potential
findings of this study are clinically relevant, as 38% of patients for targeting therapy.