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114 Part II Cellular Basis of Hematology

patients is polycythemia vera (PV); a single mutation results in the
Preleukemic Stem Cells
substitution of phenylalanine for valine at codon 617 of the Janus
Hematopoietic stem cells (HSCs) are rare (~1–2 per 10 bone marrow kinase 2 (JAK2) tyrosine kinase in nearly every patient. Targeted
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cells) and quiescent cells that rarely divide. However, all blood cells sequencing of JAK2 in patients with PV showed that the JAK2V617F
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originate from progenitor cells that in turn originate from HSCs and mutation is present in cells with an HSC phenotype (Fig. 10.1).
thus HSCs must replicate/self-renew to continue the cycle. Mutations Moreover, HSCs from patients with PV are skewed toward the ery-
in HSCs can therefore occur during cell division and accumulate, throid lineage at the HSC level already and there is also an expansion
sometimes speeding self-renewal divisions and leading to clonal of the CMP pool, suggesting that expression of the JAK2V617F
hematopoiesis. Although able to confer a growth advantage to clones mutation affects HSC and progenitor cell populations. Interestingly,
derived from mutated HSCs, these single mutations alone are not early efforts to study the effects of JAK inhibition in PV revealed that
sufficient to transform cells, resulting in an overt malignant phenotype. JAK inhibition exhibited inhibitory effects on the erythroid potential
Because growth promoting gene mutations are common in cancer, it
is thought that HSCs with mutations that cause clonal hematopoiesis of PV HSCs but did not result in preferential eradication of
might exist as preleukemic stem cells in patients with leukemia for JAK2V617F-mutant HSCs versus normal HSCs. Thus this finding
months to years prior to diagnosis. Cooperative driver mutations are of an HSC origin for PV has direct therapeutic implications, as
then acquired that cause cancer to develop. Recent publications have curative eradication of the disease would require therapy that elimi-
reported that somatic mutations causing clonal hematopoiesis exist in nates rare quiescent bone marrow–based HSCs.
healthy persons and increase in frequency with age. 14–16 The risk of a
hematologic malignancy is higher in patients with clonal hematopoiesis
compared with matched controls, providing evidence for leukemic pre- ACUTE LYMPHOBLASTIC LEUKEMIA
disposition. The most common mutations causing clonal hematopoiesis
were found in the genes ASXL1, DNMT3A, and TET2, which are also
known to be recurrently mutated in myeloid malignancies. These genes Unlike the myeloid malignancies, it has been less clear whether
encode proteins involved in epigenetic modifications of chromatin and lymphoid malignancies also arise from an HSC or have a different
DNA. Functional experiments have shown that DNMT3A and TET2 cell-of-origin. In B-cell acute lymphoblastic leukemia (B-ALL),
actually increase the number of HSCs in the bone marrow through considerable effort has gone into answering this question (Fig. 10.2).
impaired differentiation and increased self-renewal, respectively. Early studies in specific subtypes of B-ALL supported a preleukemic
Studies of a few patients with preleukemic stem cells who went on to stem cell such as identified in AML. TEL/AML-1 rearranged ALL has
develop leukemia were able to show that at least in some cases, the been particularly well studied and is associated with a good prognosis.
leukemia developed only after acquisition of another driver mutation These studies showed that TEL/AML-1 alone is insufficient for leu-
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such as mutations in FLT3. Additionally, different somatic mutations kemogenesis. In fact, the frequency of TEL/AML-1 in healthy infants
drive distinct patterns of clonal hematopoiesis, such as mutations in the
splicing factors SF3B1 and SRSF2, which exclusively occur in patients far exceeds the incidence of ALL, suggesting that the development of
over the age of 70 and may only confer a growth advantage under the leukemia requires a second hit. This is evident from studies of pairs
selection pressures of an aging hematopoietic system. 18,19 of twins, both with evidence of a preleukemic TEL/AML-1
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CD34 CD38 CD19 population of cells, where one twin developed
ALL and the other did not. The healthy twin retained the preleukemic
population, which showed evidence of self-renewal and hierarchical
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all of the mutations found in the Lin CD34 CD38 CD90 CD45RA differentiation. Later studies of high-risk ALL showed that leukemo-
MDS initiating cells have also been identified in downstream GMPs genic potential may also be present in more differentiated cell popula-
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and MEPs. These findings suggest that MDS is propagated by a tions, such as CD34 CD19 cells (Fig. 10.2). Recent extension of
stem cell that develops and acquires mutations at an early stage in this work to B-ALL cases with a variety of chromosomal abnormali-
the disease. ties have found that even mature blasts expressing CD20 were able
to establish leukemia upon transition into immunodeficient mice.
Also, as many as 1 in 40 B-ALL blasts retained leukemogenic poten-
MYELOPROLIFERATIVE NEOPLASMS tial. Overall, B-ALL blasts do not seem to be hierarchically arranged
in a similar fashion as AML and engraftment of further differentiated
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The translocation between chromosomes 9 and 22, the so-called CD34 blasts can give rise to both CD34 and CD34 populations
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Philadelphia chromosome, is the hallmark of CML and gives rise to in vivo. Together, these data suggest that B-ALL arises in a commit-
the BCR-ABL oncogene and its constitutively active protein tyrosine ted lymphoid progenitor rather than only a small population of cells
kinase product p210 BCR-ABL . In patients with CML, there is a clonal accumulating mutations and retaining stem cell properties, and that
expansion of HSCs and the BCR-ABL translocation can be detected most or even all of the leukemic blasts retain the ability to propagate
in HSCs from patients with CML as well as all myeloid as well as the malignancy.
even committed lymphoid cells generated by these HSCs (Fig. 10.1). In contrast to TEL/AML-1, those patients with ALL carrying the
This data clearly identifies chronic phase CML as a stem cell disorder BCR-ABL fusion protein have much worse clinical outcomes.
in which the target cell of transformation is a HSC. This is a finding However, like TEL/AML-1, BCR-ABL is also thought to be a primary
that has direct therapeutic implications as ABL kinase inhibitors, mutation that is necessary but not sufficient for ALL transformation.
which are used clinically for CML, do not consistently eradicate the Interestingly, the two BCR-ABL transcripts, P190 and P210, caused
quiescent BCR-ABL–positive CML LICs. by different break points in the t(9;22) translocation, show distinct
In contrast to the chronic phase of CML where the normal HSC patterns of HSC and committed B-cell progenitor involvement. In
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appears to be the target cell-of-origin, transformation of CML to the most cases, the P190 BCR-ABL originates in a CD34 CD38 CD19
myeloid blast crisis appears to be associated with expansion of a more progenitor cell while P210 BCR-ABL originates in a multipotent
committed myeloid progenitor population (which consists mostly of HSC. When purified P210 BCR-ABL HSCs were transplanted into
GMPs) rather than expansion of the HSC population. The GMPs NOD/SCID mice, they exclusively reconstituted normal, BCR-ABL–
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from blast crisis patients with CML actually have the ability to serially negative multilineage hematopoiesis. These data suggest that the
replate in vitro, a proxy of aberrant self-renewal capacity not seen in purified HSC also contained normal HSCs that outcompeted the
normal GMPs. These data suggest that disease progression from P210 BCR-ABL HSCs, which are not the leukemia stem cells. In
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chronic phase to myeloid blast crisis occurs due to aberrant acquisi- contrast, more committed CD19 P210 BCR-ABL–positive cells
tion of self-renewal potential within the committed GMP population, resulted in leukemic reconstitution upon transplantation into NOD/
a possibility which has been directly studied in animal models (Pink SCID mice that was enhanced following secondary transplant. These
Box 10.2). data complement recent findings suggesting that the primary
The other chronic myeloproliferative neoplasm besides CML in BCR-ABL translocation in CML originates in HSCs, yet the leuke-
which a specific genetic alteration is present in nearly 100% of mic transformation in blast crisis results in an LSC with a committed