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150 Part II Cellular Basis of Hematology

neutrophils. The term WHIM is an acronym for the main signs essential role of SDF-1/CXCR4 and CXCL2/CXCR2 signaling in
of the syndrome: warts, hypogammaglobulinemia, infections, and the regulation of neutrophil egress and retention.
myelokathexis; myelokathexis refers to impaired egress of mature Successful BM reconstitution requires directed stem cell migration
neutrophils and other myeloid cells from the BM, causing neutrope- from the circulation across the blood–BM barrier, and lodgment in
nia. Al Ustwani et al (2014), Beaussant et al (2012), and Dotta et al the specialized BM niches wherein stem cells proliferate and dif-
(2011) reported that the signature pathogen in WHIM syndrome ferentiate, while maintaining a small pool of primitive stem cells
is human papillomavirus (HPV), which causes warts that cannot (see Fig. 14.1).
be controlled with standard medical treatment and may progress Currently, there are multiple hypotheses regarding the defined
to cancer. Prophylactic antibiotics and G-CSF are often used to entity of the HSPC niche. SDF-1, which has a prominent role in
reduce the frequency of infections; however, their specific efficacy homing, mobilization, retention, and quiescence of HSPCs, is highly
has not been established. This syndrome confirms a crucial role expressed by endosteal osteoblasts, MSPCs, and other stromal cell
for CXCR4 signaling in neutrophil trafficking from the BM. In types, implying the importance of regulating the niche in order
the majority of cases, WHIM syndrome is caused by truncation to induce mobilization. The retention capacity of HSPCs in the
mutations in a domain important for CXCR4 downregulation BM during mobilization is altered due to several signaling events,
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(reviewed by Day and Link ). These mutations confer enhanced chemotactic gradients (e.g., SDF-1 and S1P), as well as breakdown
responsiveness to SDF-1, suggesting a model in which increased of adhesion interactions. Proteolytic enzymes that degrade adhesion
CXCR4 signaling leads to increased retention of neutrophils in the molecules or extracellular matrix components, thus promoting adher-
BM. Dale et al (2011) and McDermott et al (2011) demonstrated ence to the BM niches, are a key mechanism that enables egress of
safety and preliminary evidence of clinical efficacy in phase I studies cells to the peripheral blood. Mimicry of this process by mobilizing
of the specific CXCR4 antagonist AMD3100 (plerixafor [Mozobil]) agents leads to HSPC mobilization, and therefore such procedures
in WHIM syndrome, which increases the numbers of neutrophils can be utilized to clinically harvest repopulating HSPCs from the
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in the circulation (reviewed by Link ). Spontaneous remission or blood. Various BM-resident cellular players, including neutrophils,
cure of WHIM syndrome has been reported in 2015. McDermott osteoclasts, and osteoblasts, play significant roles in mediating physi-
et al (2015) describe chromothripsis (chromosome chattering) in one ological cell egress and stress-induced mobilization to the peripheral
patient with WHIM syndrome that deleted one copy of chromosome blood (see Fig. 14.2). Mutual interactions and effects between these
2, including deletion of the disease allele CXCR4 R334X in a single players result in a complex microenvironmental niche that regulates
HSC. Because CXCR4 regulates stem cell quiescence and the cell HSPC function, retention, and migration. Suppression of osteo-
cycle, this led to their increased proliferation and differentiation due blasts, MSPCs, or both, resulting in decreased SDF-1 expression
to a missing copy of CXCR4. This clone took over the BM and in the BM, seems to be a major mechanism by which detachment
resorted normal immune function, which resulted in cure of the of HSPCs is enabled as part of their recruitment to the peripheral
disease. This study suggests that partial CXCR4 inactivation might blood. Hence, BM niches are dynamic and undergo alterations on
enhance clinical BM repopulation in transplanted patients. 30 demand, directly affecting hematopoiesis and motility. Additionally,
there exist significant data implying a major contribution of innate
immunity in mobilizing HSPCs (e.g., by neutrophils; see Fig. 14.2).
CONCLUDING REMARKS This interplay is evident by studies showing activation of neutrophils
upon administration of mobilizing agents, such as G-CSF. Disrup-
This chapter discusses the mechanisms and pathways involved in the tion of CXCR4 signaling is an important mechanism by which
regulation of HSPC homing, egress, and mobilization, emphasizing neutrophils and HSPCs are mobilized into the circulation under
the major roles of the SDF-1/CXCR4 axis in the regulation of these stress conditions. CXCL2 is a secondary chemokine that, together
complex interactive processes. In addition, this chapter discusses the with SDF-1, controls neutrophil trafficking from the BM.

Relevance to Clinical Hematology

Optimal HPSC migration from the BM to the circulation (mobilization) chemotherapy; or alternatively, allogeneic BMT, performed for the most
for donor cell transplant harvest and from the recipient blood into the part in the setting of marrow-infiltrating malignancies such as leukemia,
BM (homing) for stem cell lodgment is an essential prerequisite for which uses donor stem cells infused to a patient, thus capitalizing on
successful BM reconstitution in clinical transplantation. As discussed in the graft-versus-leukemia effect, which affords a significant reduction in
this chapter, experimental systems involving human and murine HSPCs relapse rate. One of the major clinical obstacles facing BM transplant
enable dissection of these migration processes to identify regulatory experts today is the mobilization of the so-called “difficult mobilizers,”
mechanisms to improve clinical settings. Current understanding of HSPC who fail to mobilize the required amount of CD34 progenitors. Known
biology reveals that these cells home to the BM homeland, where they risk factors for insufficient numbers of HSPCs after mobilization include
proliferate and differentiate, giving rise to multilineage hematopoietic cells older age, previous failed mobilization, heavy BM infiltration by tumor
while maintaining a small pool of primitive stem cells. The majority of cells, and previous chemotherapy and radiotherapy, to name just a
HSPCs remain confined to the BM cavity in a nonmotile mode, adjacent few. Several strategies have attempted to address this clinical problem
to niche-supportive cells that preserve them in a quiescent, nonprolifera- using optimized current mobilization protocols, among them high-dose
tive mode, but a very low level of primitive progenitors and stem cells also G-CSF regimens, erythropoietin, SCF, and chemomobilization achieved
continuously egress to the circulation as part of homeostasis. The levels by chemotherapy treatment combined with G-CSF. Despite the wide
of these rare migrating HSPCs are dramatically enhanced during alarm gamut of therapeutic strategies used, most of them have either failed to
situations caused by injury and inflammation as part of the host defense show a clear advantage compared with standard mobilization regimens
and repair mechanism. The physiologic process of enhanced HSPC or were associated with substantial adverse effects (chemomobilization).
recruitment from the BM has been used clinically to accelerate stem and With the recent introduction of the CXCR4 antagonist AMD3100 (also
progenitor cell migration to the circulation. Thus collection of HSPCs from termed plerixafor [Mozobil]), there is renewed optimism in the manage-
the donor’s peripheral blood, rather than from their BM, became the most ment of difficult-to-mobilize patients. AMD3100 mediates rapid secre-
common clinical protocol for BM transplantation (BMT). tion of SDF-1 from BM stromal cells and its release to the circulation,
+
Clinical BMT has gained immense success within the past four decades resulting in CD34 progenitor mobilization. Treatment with AMD3100
in the treatment of malignant hematologic diseases and immunodefi- exhibits marked synergism with G-CSF, suggesting their different and
ciency states by providing long-term immune recovery after high-dose complementary mechanisms of action to induce HSPC mobilization.
chemotherapy. The basic premise in BMT is either using a patient’s Several studies have shown its success in mobilization of previously
own stem cells (i.e., autologous BMT), which are used primarily as failed myeloma in non-Hodgkin lymphoma and Hodgkin lymphoma
stem cell support for myeloma or lymphoma while undergoing intensive patients.