# 31 - 101 Hematopoietic Stem Cells

### 101 Hematopoietic Stem Cells

traditionally been performed by oncologists, but the magnitude of the 
problem mandates that primary care providers and preventive medi­
cine specialists be trained in the follow-up of treated cancer patients 
in remission or undergoing chronic therapy. All former cancer patients 
should undergo surveillance for recurrence and second malignancies 
and be monitored for long-term effects of treatment; however, nearly 
all recurrences are detected because of symptoms. Health promotion 
and disease prevention with age- and sex-specific routine screening 
tests (e.g., colonoscopy, Pap smears, mammography, human papillo­
mavirus vaccination, dual-energy x-ray absorptiometry scans) should 
be a focus of survivorship care along with psychosocial well-being. 
Annual mammography should start no later than 10 years after breast 
radiation. Patients receiving radiation fields encompassing thyroid tis­
sue should have regular thyroid examinations and TSH testing. Local­
ized pain or palpable abnormality in a previously radiated field should 
prompt radiographic evaluation. Patients treated with alkylating agents 
or topoisomerase inhibitors should have a complete blood count every 
6–12 months, and cytopenias, abnormal cells on peripheral smear, or 
macrocytosis should be evaluated with bone marrow biopsy and aspi­
rate and include cytogenetics, flow cytometry, or fluorescence in situ 
hybridization (FISH) studies as appropriate.

As the population of cancer survivors increases and patients live 
longer, cancer survivorship has become increasingly important, and 
the Institute of Medicine and National Research Council have pub­
lished a monograph entitled From Cancer Patient to Cancer Survivor: 
Lost in Transition. The monograph proposes a plan that would inform 
clinicians caring for cancer survivors of the complete details of patients’ 
previous treatments, complications thereof, signs and symptoms of late 
effects, and recommended screening and follow-up procedures.
PART 4
Oncology and Hematology
OUTLOOK
Survivorship care is a burgeoning problem facing oncologists today. 
The challenge is to develop cancer treatments that maximize clini­
cal benefit including cure of disease while also mitigating the risks 
of long-term toxicity. As cancer treatments continue to improve, the 
prevalence of cancer survivors increases along with an increase in life 
expectancy. Further, since emerging therapies often have improved 
tolerability profiles, a greater number of patients with advanced age or 
comorbid medical conditions will become cancer survivors with per­
sistent treatment-related toxicities. As treatment paradigms continue to 
evolve, the nature and biologic basis for toxicities will change and phar­
macovigilance of new therapies is critical. Advances in genomic medi­
cine may allow for more risk-stratified personalized care. The choice of 
therapy needs to be tailored to the type of cancer, expected outcomes, 
and patient-related risk factors for both acute and long-term toxicities. 
After therapy is complete, longitudinal monitoring of the health and 
health-related quality of life of cancer survivors is critical since the inci­
dence of late effects of treatment does not appear to plateau over time.
Acknowledgment
We would like to acknowledge the contribution of Carl E. Freter who 
coauthored a previous version of this chapter; material from his chapter 
was retained in this version.
■
■FURTHER READING
Armenian SH et al: Cardiovascular disease in survivors of childhood 
cancer: Insights into epidemiology, pathophysiology, and prevention. 
J Clin Oncol 36:2135, 2018.
Brinkman TM et al: Psychological symptoms, social outcomes, 
socioeconomic attainment, and health behaviors among survivors 
of childhood cancer: Current state of the literature. J Clin Oncol 
36:2190, 2018.
Chow EJ et al: New agents, emerging late effects, and the development 
of precision survivorship. J Clin Oncol 36:2231, 2018.
Ehrhardt MJ et al: Health care transitions among adolescents and 
young adults with cancer. J Clin Oncol 42:743, 2024.
Lustberg MB et al: Mitigating long-term and delayed adverse events 
associated with cancer treatment: Implications for survivorship. Nat 
Rev Clin Oncol 20:527, 2023.

Rowland JH et al: Survivorship science at the NIH: Lessons learned 
from grants funded in fiscal year 2016. J Natl Cancer Inst 111:109, 
2019.
Shapiro CL: Cancer survivorship. N Engl J Med 379:2438, 2018.
Shapiro CL et al: ReCAP: ASCO core curriculum for cancer survivor­
ship education. J Oncol Pract 12:e08, 2016.
Shree T et al: Impaired immune health in survivors of diffuse large 
B-cell lymphoma. J Clin Oncol 38:1664, 2020.
Turcotte LM et al: Risk, risk factors, and surveillance of subsequent 
malignant neoplasms in survivors of childhood cancer: A review. J Clin 
Oncol 36:2145, 2018.
Section 2	 Hematopoietic Disorders
David T. Scadden, Dan L. Longo

Hematopoietic Stem 

Cells
All of the cell types in the blood and some cells in every tissue of the 
body are derived from hematopoietic (hemo: blood; poiesis: creation) 
stem cells. If the hematopoietic stem cell is damaged and can no longer 
function (e.g., due to a nuclear accident), a person would survive 
2–4 weeks in the absence of extraordinary support measures. With the 
clinical use of hematopoietic stem cells, tens of thousands of lives are 
saved each year (Chap. 119). Stem cells produce hundreds of billions 
of blood cells daily from a stem cell pool that is estimated to be only 
20,000–200,000. How stem cells do this, how they persist for many 
decades despite the production demands, and how they may be better 
used in clinical care are important issues in medicine.
The study of blood cell production has become a paradigm for how 
other tissues may be organized and regulated. Basic research in hema­
topoiesis includes defining stepwise molecular changes accompanying 
functional changes in maturing cells, aggregating cells into functional 
subgroups, and demonstrating hematopoietic stem cell regulation by 
a specialized microenvironment; these concepts are worked out in 
hematology and offer models for other tissues. Moreover, these con­
cepts may not be restricted to normal tissue function but extend to 
malignancy.
CARDINAL FUNCTIONS OF 
HEMATOPOIETIC STEM CELLS
All stem cell types have two cardinal functions: self-renewal and dif­
ferentiation (Fig. 101-1). Stem cells exist to generate, maintain, and 
repair tissues. They function successfully if they can replace a wide 
variety of shorter-lived mature cells over prolonged periods. The pro­
cess of self-renewal (see below) assures that a stem cell population can 
be sustained over time. Without self-renewal, the stem cell pool would 
become exhausted and tissue maintenance would not be possible. The 
process of differentiation leads to production of the effectors of tissue 
function: mature cells. Without proper differentiation, the integrity of 
tissue function would be compromised and organ failure or neoplasia 
would ensue.
In the blood, mature cells have variable average life spans, ranging 
from hours for mature neutrophils to a few months for red blood cells 
to many years for memory lymphocytes. However, the stem cell pool is 
the central, durable source of all blood and immune cells, maintaining 
a capacity to produce a broad range of cells from a single cell source, 
yet keeping itself vigorous over decades of life. As an individual stem 
cell divides, it has the capacity to accomplish one of three division 
outcomes: two stem cells, two cells destined for differentiation, or one 
stem cell and one differentiating cell. The former two outcomes are the

Stem cell
Self-renewal
Differentiation
Stem cell
Differentiated cells
FIGURE 101-1  Signature characteristics of the stem cell. Stem cells have two 
essential features: the capacity to differentiate into a variety of mature cell types and 
the capacity for self-renewal. Intrinsic factors associated with self-renewal include 
expression of Bmi-1, Gfi-1, PTEN, STAT5, Tel/Atv6, p21, p18, MCL-1, Mel-18, RAE28, 
and HoxB4. Extrinsic signals for self-renewal include Notch, Wnt, SHH, angiogenin, 
and Tie2/Ang-1. Based mainly on murine studies, hematopoietic stem cells express 
the following cell surface molecules: CD34, Thy-1 (CD90), c-Kit receptor (CD117), 
CD133, CD164, and c-Mpl (CD110, also known as the thrombopoietin receptor).
result of symmetric cell division, whereas the latter indicates a different 
outcome for the two daughter cells—an event termed asymmetric cell 
division. The relative balance for these types of outcomes may change 
during development and under particular kinds of demands on the 
stem cell pool.
■
■DEVELOPMENTAL BIOLOGY OF HEMATOPOIETIC 
STEM CELLS
During development, blood cells are produced at different sites. 
Initially, the yolk sac provides oxygen-carrying red blood cells and 
many of the macrophage-like cells that are resident in tissues: cells like 
microglia in the brain. The placenta and several sites of intraembryonic 
blood cell production then become involved in sequential order. These 
move from the genital ridge at a site where the aorta, gonadal tissue, 
and mesonephros are emerging to the fetal liver and then, in the sec­
ond trimester, to the bone marrow and spleen. As the location of stem 
cells changes, the cells they produce also change. The yolk sac provides 
red cells expressing embryonic hemoglobins and tissue-resident mac­
rophages. Intraembryonic sites of hematopoiesis generate stem cells, 
red cells, platelets, and the circulating cells of innate immunity. The 
production of the cells of adaptive immunity occurs then as well but 
becomes robust as the thymus forms and the bone marrow is colonized 
in the second trimester. Stem cell proliferation remains high, even in 
the bone marrow, until shortly after birth, when it appears to dramati­
cally decline. The cells in the bone marrow are thought to arrive by the 
bloodborne transit of cells from the fetal liver after calcification of the 
long bones has begun. The presence of stem cells in the circulation is 
not unique to a time window in development, however, as hemato­
poietic stem cells circulate throughout life. The time that stem cells 
spend freely circulating appears to be brief (measured in minutes in the 
mouse), but the stem cells that do circulate are functional and can be 
used for transplantation. The number of stem cells that circulate can be 
increased in a number of ways to facilitate their harvest and transfer to 
the same or a different host.
■
■MOBILITY OF HEMATOPOIETIC STEM CELLS
Cells entering and exiting the bone marrow do so through a series of 
molecular interactions. Circulating stem cells (through CD162 and 
CD44) engage the lectins (carbohydrate binding proteins) P- and 
E-selectin on the endothelial surface to slow the movement of the 
cells to a rolling phenotype. Stem cell integrins are then activated 
and accomplish firm adhesion between the stem cell and vessel wall, 
with a particularly important role for stem cell VCAM-1 engaging 
endothelial VLA-4. The chemokine CXCL12 (SDF1) interacting 
with stem cell CXCR4 receptors and ionic calcium interacting with the 

calcium-sensing receptor are important in the process of stem cells 
getting from the circulation to where they engraft in the bone marrow. 
This is particularly true in the developmental move from fetal liver to 
bone marrow.

In the adult, the role for CXCR4 is in retention of stem cells in the 
bone marrow as well as getting them there. Interrupting that retention 
process through specific molecular blockers of the CXCR4/CXCL12 
interaction, cleavage of CXCL12, or downregulation of the CXCR4 
receptor can result in the release of stem cells into the circulation. This 
process is an increasingly important aspect of recovering stem cells for 
therapeutic use as it has permitted the harvesting process to be done 
by leukapheresis rather than bone marrow punctures in the operating 
room. Granulocyte colony-stimulating factor and plerixafor, a mac­
rocyclic compound that can block CXCR4, are both used clinically to 
mobilize marrow hematopoietic stem cells for transplant.
■
■HEMATOPOIETIC STEM CELL 
MICROENVIRONMENT
The concept of a specialized microenvironment, or stem cell niche, was 
first proposed to explain why cells derived from the bone marrow of 
one animal could be used in transplantation and again be found in the 
bone marrow of the recipient. This niche is more than just a housing 
site for stem cells, however. It is an anatomic location where regula­
tory signals are provided that allow the stem cells to thrive, to expand 
if needed, and to provide varying amounts of descendant daughter 
cells. In addition, unregulated growth of stem cells may be problematic 
based on their undifferentiated state and self-renewal capacity. Thus, 
the niche also regulates the number of stem cells produced. In this 
manner, the niche has the dual function of serving as a site of nurture 
but imposing limits for stem cells: in effect, acting as both a nutritive 
and constraining home.
CHAPTER 101
Hematopoietic Stem Cells 
The niche for blood stem cells changes with each of the sites of 
blood production during development, but for most of human life, it is 
located in the bone marrow. Within the bone marrow, the perivascular 
space particularly in regions of trabecular bone serves as a niche. The 
mesenchymal and endothelial cells of the marrow microvessels pro­
duce kit ligand and CXCL12, both known to be important for hema­
topoietic stem cells. Other cell types, such as sympathetic neurons, 
nonmyelinating Schwann cells, macrophages, megakaryocytes, osteo­
clasts, and osteoblasts, have been shown to regulate stem cells, some by 
direct and others by indirect effects. Extracellular matrix proteins like 
osteopontin and heparan sulfates also affect stem cell function. The 
endosteal region appears to be particularly important for transplanted 
cells, in part because many of the mesenchymal cells and sinusoidal 
blood vessels of the central marrow are disrupted by the conditioning 
regimens used to prepare a patient for transplantation. The function­
ing of the niche as a supportive context for stem cells is of obvious 
importance for maintaining hematopoiesis and in transplantation. An 
active area of study involves determining whether the niche is altered 
in disease as experimental models have shown that mutations in niche 
cells can lead to myeloid malignancies.
■
■EXCESS CAPACITY OF HEMATOPOIETIC STEM 
CELLS
In the absence of disease, one never runs out of hematopoietic stem 
cells. Indeed, serial transplantation studies in mice suggest that suf­
ficient stem cells are present to reconstitute several animals in succes­
sion, with each animal having normal blood cell production. The fact 
that allogeneic stem cell transplant recipients also never run out of 
blood cells over decades argues that even the limiting numbers of stem 
cells provided to them are sufficient. How stem cells respond to dif­
ferent conditions to increase or decrease their mature cell production 
remains poorly understood. Clearly, negative feedback mechanisms 
affect the level of production of most of the cells, leading to the normal 
tightly regulated blood cell counts. However, many of the regulatory 
mechanisms that govern production of more mature progenitor cells 
do not apply or apply differently to stem cells. Similarly, most of the 
molecules shown to be able to change the size of the stem cell pool 
have little effect on more mature blood cells. For example, the growth

factor erythropoietin, which stimulates red blood cell production 
from precursor cells, has no effect on stem cells. Similarly, granulocyte 
colony-stimulating factor drives the rapid proliferation of granulocyte 
precursors but has little or no effect on the cell cycling of stem cells. 
Rather, it changes the location of stem cells by indirect means, altering 
molecules such as CXCL12 that tether stem cells to their niche. Mole­
cules shown to be important for altering the proliferation, self-renewal, 
or survival of stem cells, such as cyclin-dependent kinase inhibitors, 
transcription factors like Bmi-1, microRNA-processing enzymes like 
Dicer, or even metabolic regulators like pyruvate kinase isoforms, 
have little or different effects on progenitor cells. Hematopoietic stem 
cells have governing mechanisms that are distinct from the cells they 
generate.

■
■HEMATOPOIETIC STEM CELL DIFFERENTIATION
Hematopoietic stem cells sit at the base of a branching hierarchy of 
cells culminating in the many mature cell types that compose the 
blood and immune system (Fig. 101-2). The maturation steps leading 
to terminally differentiated and functional blood cells take place both 
as a consequence of intrinsic changes in gene expression and external, 
Stem Cells
Progenitor Cells
Lineage Committed
PART 4
Oncology and Hematology
LEF1, E2A,
EBF, PAX-5
Common
Lymphoid
Progenitor
B-Cell
Progenitor
IL7
NOTCH1
IL7
T/NK Cell
Progenitor
IKAROS
PU1
IL7
Lymphomyeloid
Potent
Progenitor
Hematopoietic
stem cell
cMyb
Multipotent
Progenitor
Hox, Pbx1,
SCL, GATA2,
NOTCH
Granulocyte
Monocyte
Progenitor
SCF
TPO
GM-CSF
GATA1, FOG
NF-E2, SCL
Rbtn2
Common
Myeloid
Progenitor
IL3, SCF
TPO
Megakaryocyte
Progenitor
Megakaryocyte
Erythroid
Progenitor
FIGURE 101-2  Hierarchy of hematopoietic differentiation. Stem cells are multipotent cells that are the source of all descendant cells and have the capacity to provide 
either long-term (measured in years) or short-term (measured in months) cell production. Progenitor cells have a more limited spectrum of cells they can produce and are 
generally a shorter-lived, highly proliferative population also known as transient amplifying cells. Precursor cells are cells committed to a single blood cell lineage but with 
a continued ability to proliferate; they do not have all the features of a fully mature cell. Mature cells are the terminally differentiated product of the differentiation process 
and are the effector cells of specific activities of the blood and immune system. Progress through the pathways is mediated by alterations in gene expression. The regulation 
of the differentiation by soluble factors and cell-cell communications within the bone marrow niche are still being defined. The transcription factors that characterize 
particular cell transitions are illustrated on the arrows; the soluble factors that contribute to the differentiation process are in blue. This picture is a simplification of the 
process. Active research is revealing multiple discrete cell types in the maturation of B cells and T cells and has identified cells that are biased toward one lineage or 
another (rather than uncommitted) in their differentiation. EPO, erythropoietin; RBC, red blood cell; SCF, stem cell factor; TPO, thrombopoietin.

niche-directed or cytokine-directed changes in the cells. Our knowl­
edge of the details remains incomplete. As stem cells mature to pro­
genitors, precursors, and, finally, mature effector cells, they undergo a 
series of functional changes. These include the acquisition of functions 
defining mature blood cells, such as phagocytic capacity or hemoglobin 
synthesis. They also include the progressive loss of plasticity (i.e., the 
ability to become other cell types). For example, some myeloid progeni­
tors can make all cells in the myeloid series but none in the lymphoid 
series. As common myeloid progenitors mature, they become precur­
sors for either monocytes and granulocytes or erythrocytes and mega­
karyocytes, but not both. Some amount of reversibility of this process 
may exist early in the differentiation cascade, but that is lost beyond a 
distinct stage in normal physiologic conditions.
As cells differentiate, they may also lose proliferative capacity 
(Fig. 101-3). Mature granulocytes are incapable of proliferation and 
only increase in number by increased production from precursors. The 
exceptions to the rule are some tissue-resident macrophages, which 
appear capable of proliferation, and lymphoid cells. Lymphoid cells 
retain the capacity to proliferate but have linked their proliferation to 
the recognition of particular proteins or peptides by specific antigen 
Mature Cells
Precursors
Aiolos,
PAX-5, AML-1
B Cell
IL4
T-Cell
Progenitor
IKAROS,
NOTCH,CBF1
E2A, NOTCH1,
GATA3
T Cell
IL2
IL7
NOTCH1
Id2, Ets-1
IL7
NK Cell
IL15
NK Cell
Progenitor
Plasmacytoid
Dendritic Cell
FLT-3 Ligand
Monocytoid
Dendritic Cell
RelB, ICSBP, ld2
FLT-3 Ligand
Egn1, Myb
Monocyte
M-CSF
Monocyte
Progenitor
Granulocyte
C/EBPα
G-CSF
Basophil
IL3, SCF
Granulocyte
Progenitor
Mast Cell
C/EBPε
IL5
Eosinophil
Erythrocyte
Progenitor
GATA1
RBCs
EPO
EPO
Fli-1
AML-1
TPO
Platelets
TPO

Stem
Precursor
Progenitor
Mature
Differentiation state
More
Less
Self-renewal ability
Proliferation activity
Lymphoid 
exception
(memory B 
and T cells)
FIGURE 101-3  Relative function of cells in the hematopoietic hierarchy. The boxes 
represent distinct functional features of cells in the myeloid (upper box) versus 
lymphoid (lower box) lineages.
receptors on their surface. Like many tissues with short-lived mature 
cells such as the skin and intestine, blood cell proliferation is largely 
accomplished by a more immature progenitor population. In general, 
cells within the highly proliferative progenitor cell compartment are 
also relatively short-lived, making their way through the differentia­
tion process in a defined molecular program involving the sequential 
activation of particular sets of genes. For any particular cell type, the 
differentiation program is difficult to speed up. The time it takes for 
hematopoietic progenitors to become mature cells is ~10–14 days in 
humans, evident clinically by the interval between cytotoxic chemo­
therapy and blood count recovery in patients.
Although hematopoietic stem cells are generally thought to have the 
capacity to form all cells of the blood, individual stem cells are hetero­
geneous in their differentiation potential. That is, some stem cells are 
“biased” to become mature cells of a particular type. In addition, indi­
vidual stem cells may respond differently to proliferation or cell death 
signals. Therefore, the stem cell population is an aggregate of cells with 
somewhat distinctive properties that have the collective characteristics 
ascribed to hematopoietic stem cells.
■
■SELF-RENEWAL AND CLONAL DYNAMICS
Self-renewal is the ability to divide while preserving an undifferentiated 
state. This stem cell characteristic is generally not seen in progenitor or 
mature cells where proliferation is coupled with progressive differen­
tiation. Stem cells being able to asymmetrically divide, such that one 
daughter cell is the product of self-renewal and the other enters into 
the differentiating progenitor pool, enables the hematopoietic system 
to have a modestly sized pool of stem cells yet produce seven orders of 
magnitude greater numbers of mature blood cells each day.
Self-renewal has its risks, however. Genetic mutations that occur in 
a stem cell will durably persist in stem cells because of self-renewal. 
In contrast, mutations in progenitors will largely be lost as the cells 
terminally differentiate and die. It is the stem cell then that has greater 
potential to accumulate genetic mutations, a setting that can lead to 
cancer. Countering this risk is the small number of stem cells, the 
radioprotective environment of their bone localized niche, and the 
relative quiescence of stem cells.
Stem cells have distinctive cell cycle regulation. Some are deeply qui­
escent, serving as a deep reserve, whereas others are more proliferative 
and replenish the short-lived progenitor population. Hematopoietic 
stem cells are generally cytokine-resistant, remaining dormant even 
when cytokines drive bone marrow progenitors to proliferation rates 
measured in hours. Stem cells, in contrast, are thought to divide at far 
longer intervals, measured in months to years, for the most quiescent 
cells. This quiescence is difficult to overcome in vitro, limiting the abil­
ity to effectively expand human hematopoietic stem cells. The process 

may be controlled by particularly high levels of cyclin-dependent 
kinase inhibitors like p57 or CDKN1c that restrict entry of stem cells 
into the cell cycle by blocking the G1-S transition. Exogenous signals 
from the niche also appear to enforce quiescence, including angio­
genin, interleukin 18, and perhaps angiopoietin 1.

Individual stem cells may vary in their proliferation and self-renewal 
features. This can lead to distortions in the representation of any given 
clone of stem cells, a feature commonly seen with aging and often 
associated with acquired somatic mutations. Hematopoietic stem cells 
are estimated to acquire 17 somatic mutations with each year of life 
based on deep sequencing studies. Some of these appear to provide a 
fitness advantage to the stem cell as the presence of mutated or “variant” 
alleles contributing to >1% of blood cells is virtually uniform by age 70. 
Furthermore, it is estimated that 10–20 such clones exist in individuals 
by 70, and in aggregate, those clones provide between 30 and 60% of 
the blood cells. Thus, the diversity of active stem cell clones declines 
with age with a likely accompanying reduced diversity of functions that 
each clone provides. Whether this contributes to immune alterations or 
other aspects of aging is to be determined. However, some expanded 
clones are associated with “driver” mutations observed in myelodys­
plasia and myeloid leukemias. These clones do have a low frequency 
of progression to overt neoplastic disease, and at least one of them, 
an inactivating mutation of TET2, can also increase adverse outcomes 
from a number of chronic inflammatory conditions.
CHAPTER 101
The most common mutations associated with clonal hematopoiesis 
are of epigenetic regulatory genes. For example, inactivating mutations 
of the DNA methyl transferase DNMT3a or the dioxygenase involved 
in DNA demethylation, TET2, are commonly found, as are mutations 
in ASXL1, a member of the polycomb family of genes whose products 
alter chromatin structure, a high-order DNA organization that affects 
transcription. Therefore, epigenetic control appears to be critical for 
homeostasis of the hematopoietic stem cell pool and constraining the 
outgrowth of potentially pathogenic stem cell clones.
Hematopoietic Stem Cells 
THE RELATIONSHIP OF STEM CELLS TO 
CANCER
Some cancers have been shown to have a cellular hierarchy similar to 
normal tissues, with stem-like cells having the capacity to self-renew 
and differentiate. These stem-like cells can be experimentally trans­
planted into immunodeficient animals and initiate a new cancer. It 
is hypothesized that these stem-like cells may be the basis for disease 
relapse after therapy as they have distinctive molecular features from 
other cells in the cancer that may render them less vulnerable to 
therapies. Myeloid leukemias have been experimentally shown to be 
consistent with this model. Focusing therapies on the stem-like cells 
as opposed to the bulk population of the cancer cells as a means to 
improve cure rates is an active area of investigation.
Given that hematopoietic stem cells can accumulate genetic muta­
tions by virtue of their self-renewal, it is logically appealing to regard 
them as the likely cell source of leukemias. Experimental testing of 
this hypothesis has shown that stem cells are more likely to result in 
malignancy following an oncogenic mutation. However, some more 
mature populations with less well-defined self-renewal capability can 
also be transformed to malignancy. Therefore, self-renewal may also 
be acquired by mutation, and cancer stem-like cells need not have 
originated in normal stem cells.
STEM CELLS AS TARGETS OF GENE 
THERAPY OR GENE EDITING
The hematopoietic stem cell is the ideal cell target for genetic therapies 
intended to durably change the genome of blood cells. Because stem 
cells can persist for the lifetime of an individual, genetically modify­
ing them can provide curative therapies for genetic disorders such as 
hemoglobinopathies or congenital immunodeficiencies. The extensive 
cell proliferation with limited or no self-renewal among progenitor 
populations makes them less able to provide durable benefit if they 
are genetically modified. Therefore, modification of stem cells is criti­
cal and requires integration of the genetic therapy into the host cell’s