Leukemic blast cells and controversies in models of hematopoiesis
Classical and up-to-date models of hematopoietic lineage determination are briefly reviewed with the focus on myeloid-based models challenging the existence of the common progenitor for T cells, B cells and NK cells. The analysis of immunophenotype of leukemic blast cells seems to be a promising app...
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irk-123456789-1453902019-01-22T01:23:32Z Leukemic blast cells and controversies in models of hematopoiesis Gluzman, D.F. Sklyarenko, L.M. Zavelevich, M.P. Koval, S.V. Ivanivskaya, T.S. Reviews Classical and up-to-date models of hematopoietic lineage determination are briefly reviewed with the focus on myeloid-based models challenging the existence of the common progenitor for T cells, B cells and NK cells. The analysis of immunophenotype of leukemic blast cells seems to be a promising approach for interpreting some controversies in the schemes of normal hematopoiesis. The literature data as well as our own findings in the patients with various types of acute leukemias are in favor of the concept postulating that common myeloid-lymphoid progenitors giving rise to T and B cell branches retain the myeloid potential. The similarity of some immunophenotypic features of blast cells in pro-B acute lymphoblastic leukemia and acute monoblastic leukemia is consistent with monocyte origin postulated in the studies of normal hematopoiesis. Study of acute leukemias may be the challenging area of research allowing for new insight into the origin of hematopoietic cell lineages. Key Words: models of hematopoiesis, leukemic stem cell, immunophenotype, acute leukemias. 2015 Article Leukemic blast cells and controversies in models of hematopoiesis / D.F. Gluzman, L.M. Sklyarenko, M.P. Zavelevich, S.V. Koval, T.S. Ivanivskaya // Experimental Oncology. — 2015. — Т. 37, № 1. — С. С. 2-4. — Бібліогр.: 23 назв. — англ. 1812-9269 http://dspace.nbuv.gov.ua/handle/123456789/145390 en Experimental Oncology Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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Reviews Reviews Gluzman, D.F. Sklyarenko, L.M. Zavelevich, M.P. Koval, S.V. Ivanivskaya, T.S. Leukemic blast cells and controversies in models of hematopoiesis Experimental Oncology |
| description |
Classical and up-to-date models of hematopoietic lineage determination are briefly reviewed with the focus on myeloid-based models challenging the existence of the common progenitor for T cells, B cells and NK cells. The analysis of immunophenotype of leukemic blast cells seems to be a promising approach for interpreting some controversies in the schemes of normal hematopoiesis. The literature data as well as our own findings in the patients with various types of acute leukemias are in favor of the concept postulating that common myeloid-lymphoid progenitors giving rise to T and B cell branches retain the myeloid potential. The similarity of some immunophenotypic features of blast cells in pro-B acute lymphoblastic leukemia and acute monoblastic leukemia is consistent with monocyte origin postulated in the studies of normal hematopoiesis. Study of acute leukemias may be the challenging area of research allowing for new insight into the origin of hematopoietic cell lineages. Key Words: models of hematopoiesis, leukemic stem cell, immunophenotype, acute leukemias. |
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Article |
| author |
Gluzman, D.F. Sklyarenko, L.M. Zavelevich, M.P. Koval, S.V. Ivanivskaya, T.S. |
| author_facet |
Gluzman, D.F. Sklyarenko, L.M. Zavelevich, M.P. Koval, S.V. Ivanivskaya, T.S. |
| author_sort |
Gluzman, D.F. |
| title |
Leukemic blast cells and controversies in models of hematopoiesis |
| title_short |
Leukemic blast cells and controversies in models of hematopoiesis |
| title_full |
Leukemic blast cells and controversies in models of hematopoiesis |
| title_fullStr |
Leukemic blast cells and controversies in models of hematopoiesis |
| title_full_unstemmed |
Leukemic blast cells and controversies in models of hematopoiesis |
| title_sort |
leukemic blast cells and controversies in models of hematopoiesis |
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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2015 |
| topic_facet |
Reviews |
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http://dspace.nbuv.gov.ua/handle/123456789/145390 |
| citation_txt |
Leukemic blast cells and controversies in models of hematopoiesis / D.F. Gluzman, L.M. Sklyarenko, M.P. Zavelevich, S.V. Koval, T.S. Ivanivskaya // Experimental Oncology. — 2015. — Т. 37, № 1. — С. С. 2-4. — Бібліогр.: 23 назв. — англ. |
| series |
Experimental Oncology |
| work_keys_str_mv |
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2025-07-10T21:34:12Z |
| last_indexed |
2025-07-10T21:34:12Z |
| _version_ |
1837297312746962944 |
| fulltext |
2 Experimental Oncology 37, 2–4, 2015 (March)
LEUKEMIC BLAST CELLS AND CONTROVERSIES
IN MODELS OF HEMATOPOIESIS
D.F. Gluzman*, L.M. Sklyarenko, M.P. Zavelevich, S.V. Koval, T.S. Ivanivskaya
R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, NAS of Ukraine, Kyiv 03022, Ukraine
Classical and up-to-date models of hematopoietic lineage determination are briefly reviewed with the focus on myeloid-based
models challenging the existence of the common progenitor for T cells, B cells and NK cells. The analysis of immunophenotype
of leukemic blast cells seems to be a promising approach for interpreting some controversies in the schemes of normal hematopoi-
esis. The lite rature data as well as our own findings in the patients with various types of acute leukemias are in favor of the concept
postulating that common myeloid-lymphoid progenitors giving rise to T and B cell branches retain the myeloid potential. The si-
milarity of some immunophenotypic features of blast cells in pro-B acute lymphoblastic leukemia and acute monoblastic leukemia
is consistent with monocyte origin postulated in the studies of normal hematopoiesis. Study of acute leukemias may be the chal-
lenging area of research allowing for new insight into the origin of hematopoietic cell lineages.
Key Words: models of hematopoiesis, leukemic stem cell, immunophenotype, acute leukemias.
HISTORICAL BACKGROUND
Unitary theory of hematopoiesis put forward by A. Ma-
ximow more than a century ago has an exceptional place
in the history of oncohematology [1]. Based on his semi-
nal experimental histological findings, A. Maxi mow was
the first to postulate the existence of a single parental cell
common for all three lineages of hematopoiesis, namely
lymphoid, myeloid and erythroblastoid. While the question
whether or not all blood cells derive from a single precursor
cell was a subject of consi derable debate over the years,
now the monophyletic view of hematopoiesis became
generally accepted.
In 1961, the unequivocal evidence proving existence
of hematopoietic stem cell (HSC) was obtained in stu-
dies with bone marrow in lethally irradiated mice [2]. HSC
has been considered as a pluripotent cell being capable
of self-renewal and giving rise to the progenitor cells of all
lineages of hematopoiesis. Later on, HSC population has
been shown to be heterogeneous subdividing into long-
term HSCs and short-term HSCs [3]. While originally HSCs
were delineated only based on the clonal assays, later they
became phenotypically distinguishable [4].
According to the current models of lineage determina-
tion in the hematopoietic hierarchies, HSC diffe rentiation
gives rise to multipotent progenitors (MPPs) practically
devoid of self-renewal ability but retaining the potential
for multilineage differentiation. In the classical dichotomy
concept, MPP was thought to give rise to two principal
lineages of hematopoiesis, namely lymphoid and myeloid-
erythroid. Later, hypothetical lineage-restricted pro-
genitors, such as common myeloid progenitor (CMP) and
common lymphoid progenitor (CLP) have been identified
in experimental studies of hematopoiesis in mice [5, 6].
Classical dichotomic model of myeloid-lymphoid
branching vs. myeloid-based model. In classical di-
chotomic model reinforced by identification of CMP and
CLP, lymphoid and myeloid lineages diverge from MPP
as a single progenitor in a symmetrical fashion [7]. There-
fore, CMP and CLP were regarded as myeloid or lymphoid
lineage committed progenitors. Nevertheless, the classi-
cal dichotomic model was later modified since the experi-
mental findings suggest that CLP and CMP are generated
asymmetrically from different MPPs. In fact, MPPs turned
out to be heterogeneous containing the progenitors
generating two types of cells and those generating only
one type, in addition to progenitors generating myeloid,
T and B cells with varying combinations of lymphoid and
myeloid potential [8]. Moreover, prior to lymphoid lineage
commitment at CLP stage, MPPs lose myeloid lineage
differentiation potential in a stepwise fashion. Kawamoto
et al. [9] pointed out that lymphoid lineage specification
is in fact a gradual process with many intermediate states
rather than a pathway with single bifurcation.
The origin of T, B, and NK cell lineages: common
or separate progenitors? According to the classical
model, CLP is a single progenitor committed to lymphoid
lineages, namely T, B or NK cells. In other words, the exi-
stence of a single progenitor suggested a common origin
of all lymphocytes rather than a separate developmental
pathway for each lymphocyte lineage from HSCs. In clas-
sical schemes of hematopoiesis, the direct dichotomy
of B cell progenitors and T cell progenitors from CLP
was postula ted [10]. Instead, the myeloid-based model
introduces common myeloid-lymphoid progenitor (CMLP)
giving rise to T and B cell branches that retain the myeloid
potential [9]. The postulated CMLP generates T and B cell
progenitors through bipotential myeloid/T progenitor and
myeloid/B progenitor stages, respectively [11]. Acco rding
to the revised models, CMP gives rise to well-defined
populations of myelo-erythroid progenitors: granulocyte/
macrophage progenitor (GMP) and megakaryocyte/
Submitted: November 5, 2014.
* Correspondence: gluzman@onconet.kiev.ua
Abbreviations used: ALL — acute lymphoblastic leukemia; AML —
acute myeloid leukemia; BC — blast crisis; CLP — common lymphoid
progenitor; CML — chronic myelogenous leukemia; CMLP — com-
mon myeloid-lymphoid progenitor; CMP — common myeloid
proge nitor; DC — dendritic cell; GMP — granulocyte/macrophage
progenitor; HSC — hematopoietic stem cell; LSC — leukemic stem
cell; MEP — megakaryocyte/erythrocyte progenitor; MLP — multi-
lymphoid progenitor; MPP — multipotent progenitor.
Exp Oncol 2015
37, 1, 2–4
REVIEWS
Experimental Oncology 37, 2–4, 2015 (March) 3
erythrocyte progenitor (MEP) while the existence of CLP
as a progenitor with restricted B and T cell output has
not been confirmed and MLP (multilymphoid progenitor)
gi ving rise to lymphoid and myelo-monocytic lineages
was placed instead of CLP in the scheme of human he-
matopoiesis [12, 13]. Nevertheless, the precise lineage
output of each suggested MLP and the precise points
of bran ching of B, T and NK cell lineages could not
be ascertained. The cells possessing the mixed T/B po-
tential were not found out [11]. Moreover, several studies
indicate that the divergence of T cell lineage might occur
upstream of CLPs in mouse bone marrow [7]. Neverthe-
less, the exact point of bifurcation giving rise to T cells
remains highly questionable.
The exact origin of NK cells also remains questionable.
It is still unknown whether the postulated T/NK progenitor
exists. While the prevalent idea of common T/NK pathway
is supported by a series of the shared T/NK antigens and
the similarity of some functions in T and NK cells, a clo-
nogenic lymphoid progenitor with both B cell and NK cell
lineage potential has been also identified [14]. This sug-
gests that NK cell pathway may be closer to B cell rather
than T cell pathway, and these relations are in fact depicted
in some revised schemes of hematopoiesis [12].
Novel myeloid-based model of hematopoiesis
and origin of granulocytes, macrophages, and den-
dritic cells. Since the classical model of hematopoiesis
postulating a dichotomous lineage restriction of MPPs
into CLPs and CMPs has been challenged by the identi-
fication of lymphoid progenitors retaining partial myeloid
potential such as MLPs in human hematopoiesis, it was
suggested that some cells belonging to myeloid lineage
might originate from both myeloid and lymphoid (with
myeloid potential) branches [15]. A close relationship
between B cells and macrophages has been suggested
earlier from the findings that B cells and B-cell lines can
be converted into macrophages in transfection experi-
ments [16]. Doulatov et al. [13] presented evidence that
MLPs generate not only all lymphoid cell types but also
monocytes, macrophages and dendritic cells (DCs).
In other words, macrophages and DCs can be derived
from both MLPs and GMPs. All these data prompted once
again a revision of the model of hematopoiesis.
HSC and leukemic stem cell (LSC). The hierarchic
relationships in hematopoietic system have been suc-
cessfully delineated due to the functional assays based
on clonogenic analysis and later on the subtle analysis
of immunophenotype of various subpopulations of HSC
and progenitor cells. Nevertheless, the interpretation
of in vitro assays could not be regarded as unequivocal
due to various technical factors intrinsic to these assays.
Some uncertainties in establishing precise lineage poten-
tial and deline ating the exact branching points for each
lineage as well as presumable pathways and postulated
progenitors are demonstrated in various modern modified
variants of hematopoiesis schemes [7, 9, 12]. In fact, the
detailed features of certain pathways of hematopoiesis
and existence of several progenitor cells remain the point
of much controversy. Moreover, despite the obvious prog-
ress in understanding the functional properties, molecular
mechanisms of regulation of proliferation of HSCs and
hematopoietic progenitor cells, their cytomorphological
and cytochemical features remain underexplored.
In 1997, in a series of meticulous experiments the exi-
stence of the LSC was proved for acute myelo blastic
leukemia [17]. Later on, LSCs for several other biological
forms of leukemias have been identified. Now it is widely
recognized that LSC in each type of leukemia corresponds
to one or another normal counterpart representing pro-
genitor cells at various stages of lineage commitment
and differentiation in the hie rarchy of hematopoiesis.
In the recent WHO classification of tumors of hemato-
poietic and lymphoid tissues (2008), the candidate LSCs
suggested for each form of leukemias are compared with
corresponding stem cells and progenitor cells in normal
hematopo iesis [18]. It has been shown that LSCs and
HSCs share the gene expression programs [19].
Now it is generally assumed that the study of leukemic
analogs of progenitor cells in different biological types
of leukemias will be much helpful in elucidating some
questionable points in modern scheme of hematopoiesis.
The analysis of the blast cells in the patients with hemato-
logical disorders, in particularly hematological malignan-
cies, provides important data for elucidating the regulatory
mechanisms in hematopoiesis.
Challenges in interpreting controversial pathways
in modern scheme of hematopoiesis based on stu-
dying immunophenotype of leukemia blast cells.
In the group of acute leukemias of ambiguous lineage,
the recent WHO classification [18] delineates the acute
undifferentiated leukemia without expression of lineage-
specific antigens and the leukemias co-expressing
antigens of several lineages at the levels not sufficient
for identifying precisely the lineage of blast cells (acute
leukemia with mixed phenotype, including B/myeloid
leukemia, T/myeloid leukemia, lymphoblastic leukemia/
lymphoma from NK-cells). Study of these leukemias may
be the challenging area of research allowing for new insight
into the origin of lymphoid cell lineages.
The biphenotypic acute leukemias are believed to arise
from MPP cells with the capability of diffe rentiating along
both myeloid and lymphoid lineages. Previously, Matutes
et al. [20] have been shown that the most common im-
munophenotype of biphenotypic acute leukemias is a co-
expression of B-lymphoid and myeloid markers and much
less frequently, T-lymphoid and myeloid markers, while
the cases with a B and T lymphoid phenotype or with tri-
lineage differentiation are exceptional. In fact, the same
has been demonstrated in our diagnostic studies provided
in Ukraine throughout several decades [21]. In some pa-
tients with ALL from early B-cells progenitors (pro-B-ALL,
ALL of “common” type), the co-expression of a series
of myeloid antigens (CD33, CD13, CD15) was detected
that is in line with the modern concept of the persistence
of myeloid potential in lymphoid lineage branches. Never-
theless, in various immunological variants of ALL of B-cell
origin, we have never observed the co-expression of T-cell
antigens on the blasts. Similarly, in T-ALL/T-cell lym-
phoma, the blast cells have never expressed the markers
characteristic of B-cell immunophenotype.
4 Experimental Oncology 37, 2–4, 2015 (March)
Study of blast crisis (BC) in the terminal phase
of chronic myelogenous leukemia (CML) is also relevant
to the issue of the origin of T cell lineage. This final phase
in the evolution of CML behaves like an acute leukemia
of myeloid (70% of cases) or lymphoid (30% of cases)
types. In lymphoid type of BC CML, blast cells are ex-
clusively of B cell lineage with occasional co-expression
of myeloid antigens but very rare if ever expression of T cell
antigens. The blast cells of T cell phenotype in BC CML
have been never detected in our studies [21]. This is again
in line with the data that cells with double expression
of B and T cell antigens have been never found in CLP
populations in normal hematopoiesis [11]. Therefore, the
fact that blast cells simultaneously exhibiting T-cell and
B-cell surface antigens have not been observed both
in acute leukemias and in BC CML contradicts to the con-
cept of CLP as the common progenitor cell for B cell and
T cell lineages.
Some features of acute leukemias may be also con-
sidered as the helpful hints of the origin of NK cells. In our
studies some similarity between blast cells in pro-B-ALL
[МPО−, HLA-DR+, CD34+ (less than 50% of cells), CD19+
and CD33− (or their co-expression), t (4;11), 11q23] and
acute monoblastic leukemia (AML M5a) [МPО−, HLA-
DR+/−, CD34+/−, CD33+ and CD19− (or their co-expression),
t (9;11), 11q23] was found out [21]. Such similarities
of immunophenotypic features and cytogenetic abnor-
malities in blast cells in pro-B-ALL and AML M5a seem
to be the hint explaining for us three cases of AML M5a
that were presented as a relapse of leukemia in children
originally diagnosed as pro-B-ALL [23]. In some acute
leukemia patients, the blasts with expression of marker
signs of NK-cells and monocytes were detected. In our
experience, the aberrant expression of CD7 and CD56 ob-
served in 32% cases of acute monoblastic leukemia was
indicative of unfavorable course of the disease.
In our opinion, bipotent cells-progenitors of B-lym-
phocytes/monocytes and NK-cells/monocytes originate
from oligolineage progenitors of lymphocytes/mono-
cytes. At the next stage of development, the unipotent
progenitors — pro-B-lymphocytes, pro-NK-cells and
promonocytes arise, correspondingly. This is consistent
with dual monocyte origin postulated in the studies of nor-
mal hematopoiesis [13]. The data on the clonal analysis
of human acute leukemias/lymphomas with B cell/my-
elomonocytic phenotypes [22] also support the possible
existence of B cell/myelomonocytic bipotent progenitors.
To sum up, the data based on cytochemical and immu-
nophenotypical signs of leukemic blast cells may be con-
sidered as reminiscent of the corresponding data pertinent
to normal hematopoiesis. In our opi nion, the analysis
of the assembly of such data may be useful in solving some
controversies in the modern schemes of hematopoiesis
and even in amending modern hie rarchic model of normal
hematopoiesis. On the other hand, the refined schemes
of normal hematopoiesis might represent a good basis for
improvements and even revisions in up-to-date classifica-
tions of the tumors of hematopoietic and lymphoid tissues.
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