human myeloid leukemia cell lines: a review - blood

Human Myeloid Leukemia Cell Lines: A Review

344 Blood. Vol. 56. No. 3 (September), 1980

By H. P. Koeffler and D. W. Golde

Several human acute myeloid leukemia cell lines were recently established. These lines provide useful model systems to

study the control of differentiation in human myelogenous leukemia and, in a broader framework, the controls of normal

myeloid development. The K562 line is composed of undifferentiated blast cells that are rich in glycophorin and may be

induced to produce fetal and embryonic hemoglobin in the presence of hemin. The KG-i cell line is composed

predominantly of myeloblasts and promyelocytes. A unique characteristic of the KG-i cells is their almost complete

dependence on colony-stimulating factor for proliferation in soft-gel culture. The HL-60 is a promyelocytic leukemia cell

line. In the presence of DMSO. the cells mature into granulocytes. Both the KG-i and HL-60 cells differentiate into

nondividing mononuclear phagocytes when exposed to phorbol esters. Investigations with these cell lines. and selected

variants should provide important insights into the cell biology and perhaps therapy of human leukemia.

R ESEARCH in human acute myelogenous leu-

kemia (AML) has been impeded by the lack of

adequate model systems to study. Myeloid leukemia in

lower animals does not closely parallel the human

disease, and studies on fresh human leukemic cells

have been limited in part by the restricted survival of

AML cells in vitro. Murine erythroleukemia’ and

myelogenous leukemia2’3 cell lines have been estab-

lished. These lines have been useful in studying gene

expression and the modulation of hematopoietic cell

proliferation and differentiation, but they have had

more limited applicability in the investigation of the

pathophysiology of human AML.

A number of cell lines have been established from

patients with AML.47 These lines are usually

composed of poorly differentiated lymphoblastoid-

appearing cells with Epstein-Barr (EB) virus-asso-

ciated antigens and lymphocyte cell markers. The cell

lines probably arose from EB-virus transformation of

non-neoplastic lymphocytes present in the initial

culture inoculum. Recently, several human myeloid

cell lines have been established that will likely provide

the necessary tools permitting a major increase in our

knowledge of the regulation of cell growth and differ-

entiation in AML.’’#{176}

In 1975, Lozzio and Lozzio’ reported the develop-

ment of the K562 line from the pleural fluid of a

patient with chronic myeloid leukemia in blast crisis.

Collins and coworkers9 established a human myeloge-

From the Division of Hematology-Oncology, Department of

Medicine, UCLA School of Medicine, Los Angeles, and the Veter-

ans Administration Hospital, Sepulveda, Calif

Supported in part by USPHS Grants CA 15619, CA 15688, CA

16042, and CA 26038 and the Medical Research Service of the

Veterans Administration Hospital. H.P.K. is a Scholar of the

Leukemia Society of America.

Submitted October 10, 1979; accepted April 8, 1980.

Address reprint requests to H. P. Koeffler. University of Califor-

nia, Los Angeles. Department of Medicine, School of Medicine,

Centerfor the Health Sciences, Los Angeles. Calif 91343.

‘0 1 980 by Grune & Stratton, Inc.

0006-4971/80/5603-0002$0l.00/0

nous cell line designated HL-60 from the peripheral

blood of a woman with acute promyelocytic leukemia.

Active cell growth began in liquid culture supple-

mented with conditioned medium from human

embryonic lung cells. Later passages no longer

required conditioned medium for cell growth. A third

myeloid cell line, known as KG-I, was derived in our

laboratory from the bone marrow of a man with

erythroleukemia.’#{176} After 24 days in liquid culture, the

cells began active proliferation. Characteristics of the

three myeloid cell lines are summarized in Table I.

MORPHOLOGY AND HISTOCHEMISTRY

Representative Wright-Giemsa-stained prepara-

tions of the three cell lines are shown in Fig. I (A, B,

and C). The K562 cell is an undifferentiated blast cell

with a diameter of about 20 zm (Fig. I A). The cell has

a basophilic cytoplasm containing no granules and

there are two or more prominent nucleoli. The K562

cells do not stain with cytochemical reagents normally

positive in granulocytes and monocytes. Thus, there is

no reaction with peroxidase, Sudan black B, or ASD-

chloroacetate esterase stains. Many cells are strongly

reactive for acid phosphatase.

Most of the HL-60 cells are at the promyelocyte

stage of maturation and they contain prominent

azurophilic granules (Fig. I B). Myeloblasts, myelo-

cytes, and more mature granulocytic forms are occa-

sionally present. The HL-60 cells react strongly with

cytochemical stains specific for granulocytic cells,

includi ng peroxidase, AS D-chloroacetate esterase,

and Sudan black B.” The cells do not stain for alkaline

phosphatase and they appear not to contain lactofer-

nfl.

The KG-I line shows considerable pleomorphism

with most of the cells at the myeloblast and promyelo-

cyte stages, but lO%-20% of the cells are myelocytes

or mature granulocytes (Fig. IC). Occasional macro-

phages and eosinophils are also present. Clones

derived from the parent line show a similar degree of

pleomorphism. In later passages (greater than 1 .5 yr

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HUMAN MYELOID LEUKEMIA AND CELL LINES 345

Table 1 . Properties of Human Myeloi d Leukemia Cell Lines

K562 HL-60 KG-i

Source

Morphology and

histochemistry

Mean doubling time

Chromosome number

Lymphocyte markers

CSF response

Induction of dif-

ferentiation

CML in blast crisis

Undifferentiated blast

cell

1 2 hr

Modal 70 (Ph’ chromosome)

No

No

Erythroid

APL’

Promyelocyte

30-40 hr

Modal 45

No

Yes

Granulocyte or

macrophage

Erythroleukemia

Myeloblast-

promyelocyte

40-50 hr

47

No

Yes

Macrophage

APL. acute promyelocytic leukemia.

in culture), almost all of the cells are morphologically

at the myeloblast and promyelocyte stages. More than

90% of the cells stain strongly for ASD-chloroacetate

esterase, but only I%-2% are peroxidase-positive.’#{176}

The few macrophages present stain heavily for alpha

naphthyl butyrate esterase.

GROWTH KINETICS

All three cell lines grow in suspension culture as

single cells. The KG-I and HL-60 cells have a

doubling line consistent with AML cells in vivo (48-72

hr); K562 has a mean doubling time of I 2 hr.

KARYOTYPE

A prominent feature of the three cell lines is the

marked karyotypic abnormalities. Using banding

techniques, no common karyotypic abnormality is seen

in the three cell types. The K562 cells have nearly 1.5

times the normal number of chromosomes: 70 XXX,

- 13, - 17, +7, +9 (pll), plus small metacentnic

chromosome, Xp-, 3p-, 9p-, t(l5;18) (q21;q23),

r(22), or 22q- . The cells have a small ring chromo-

some r(22) or retain the Philadelphia chromosome

(22q-).’2 Several cytogenetically different clones of

HL-60 are present. The predominant karyotype is:

45x, -5, -8, - 16, -x, plus an A group marker, plus

an acrocentnic D group marker, plus a submetacentnic

E group marker.” The KG-I cells have shown a

consistent karyotype identical to the patient’s

leukemic cells: 47, xy, 7q-, 9p+, l2p+, -20,

+ MAR - 1 (large metacentnic), + MAR - 2 (small

fragment). ‘#{176}

LYMPHOCYTE MARKERS

The cells from all three lines do not have lympho-

cytic characteristics. They have no surface immuno-

globulin, Epstein-Barr virus-associated antigens, nor

do they form rosettes with sheep red cells. Only about

5% of the KG-l and HL-60 cell populations form

rosettes with erythrocytes coated with antibody (EA)

or antibody and complement (EAC). Over 90% of the

K562 cells form EA rosettes, indicating the presence

of Fc receptors. Terminal deoxynucleotidyl transfer-

ase, an enzyme present in immature lymphocytes and

rarely in AML cells, is not detectable in KG-I or

HL-60 cells.

CELL SURFACE ANTIGENS

The Ia-like or DR antigen is usually expressed on

human myeloid leukemia cells. The KG- I cells express

the antigen.’3 The antigen is not present on HL-60,

which is consistent with prior studies showing that at

the promyelocyte stage of development, the antigen is

usually lost.’3 The K562 cells also lack the Ia antigen.

There is evidence that the K562 cells are very early

erythroid precursors and that, perhaps, these cells

have not matured to the stage of Ia antigen expres-

sion.’�’6

As is the case with most hematopoietic cells, the

KG-l and HL-60 cells express HLA-A and HLA-B

antigens. The HL-60 cells are HLA-Al,8, Bl7; and

the KG- I cells express the rare antigens H LA-A30,3 1,

B35.’3 Neither HL-60 nor KG-I cells express acute

lymphocytic leukemia (ALL), granulocyte, or thymo-

cyte antigens. The K562 cell population lacks HLA,

ALL, and thymocyte antigens.

If a specific human acute myelogenous leukemia

cell-associated antibody could be isolated, it would

have great diagnostic and therapeutic potential.

Rabbit antisera have been raised to K562 and KG-l

cells and a primate antiserum was produced by immu-

nization of monkeys with K562.’7’9 The KG-I anti-

serum was produced by pretreating rabbits with anti-

leukocyte serum (ALS) and coating the immunizing

KG-I cells with antilymphocyte serum (ALS).’9 After

absorption with ALL cells, the KG- 1 antiserum

reacted with leukemic cells from 10 of 46 patients with

AML, and 2 of 23 ALL patients. The antiserum had

no activity against normal B or T lymphocytes, granu-

locytes, CML, or CLL cells, or normal granulocyte-

monocyte precursor cells (CFU-C). The K562 anti-

sera react with peripheral blood leukocytes from




346 KOEFFLER AND GOLDE

B

CFig. 1 . Morphological characteristics of cells from human AMI lines. (A) K562-undifferentiated blasts. (B) HL-60-cells at

promyelocyte stage. (C) KG-i -majority of cells are myeloblasts and promyelocytes.




125

100

wU,

+1

U)

Lu

z0-‘I0Q

75

50

25

0 GOl 011 110 10 ‘ ioo

CSF ( ul I ml

Fig. 2. Colony-stimulating factor dose-response curve.Colony formation by 5 x 10� KG-i cells is shown as a function ofCSF concentration. The CSF is 500-fold purified conditionedmedium from a continuous T-lymphocyte culture. Each point


represents the mean ± SE.

patients with CML. These antisera react with occa-

sional neoplastic lymphoid and normal myeloid cells

and, therefore, a specificity for neoplastic myeloid

antigens has not been conclusively demonstrated.

Recently, it has become possible to produce large

amounts of monoclonal, monospecific antibody by

hybridization of a myeloma cell line with hypenimmu-

nized spleen cells.2#{176}22This technique has been applied

to the development of antibodies to certain normal and

neoplastic cellular antigens. Hybridization with spleen

cells from mice immunized with the human myeloid

lines may produce useful monoclonal antibodies.

HORMONAL MODULATION

The cloned AML cell lines provide good model

systems to elucidate the interaction of hormones with

human myeloid leukemia cells. Colony-stimulating

factor (CSF) is probably an in vivo granulopoietin,

and in vitro it stimulates the proliferation and matura-

tion of early granulocyte-monocyte precursor cells

(CFU-C).23 In semisolid culture, the CFU-C are stim-

ulated by CSF to undergo a series of replicative and

maturational steps to produce a colony of mature

granulocytes or macrophages. Colony-stimulating fac-

ton stimulates colony formation by the HL-60 and

KG-I cells in vitro. A striking characteristic of the

KG-l cells is their nearly complete dependence on

CSF for colony formation in soft-gel culture’#{176}’24(Fig.

2). In the absence of added CSF, only a rare KG-i

colony forms in soft-gel culture. There is a clear

dose-response relationship between CSF concentra-

tions and the number of colonies formed. At optimal

1’150

CSF concentrations, the KG-I cells have a cloning

efficiency of 3%. The KG-i cells also respond to CSF

exposure in liquid culture with an increased 3H-

thymidine labeling index (LI) and an increased rate of

precursor incorporation into RNA and DNA.24’25 We

have utilized the CSF-dependent stimulation of

thymidine incorporation by KG- 1 to develop a sensi-

tive microassay for human CSFs; the assay is quanti-

tative and requires only I day as compared with 10-14

days for conventional colony formation assays.25 CSF

has no effect on KG-l cell maturation. A stable

subline of the KG- I line spontaneously developed from

the parent line and shows little response to CSF.26

These cells are morphologically and functionally

undifferentiated blast cells. The cells retain a number

of constitutive markers of the parent cells.

The HL-60 cells are capable of forming colonies of

promyelocytes in the absence of any added factor with

a plating efficiency of approximately 3,5%,27 The

addition of CSF increased colony number approxi-

mately 2-3-fold. The K562 cells form colonies in

soft-gel culture, but do not respond to CSF. The KG-I

and HL-60 lines and their variants provide a homoge-

neous cell population to study the mechanism of CSF

action at the cellular level and investigations of a

cellular CSF receptor will be possible.

The effect of other hormones on myeloid leukemia

cell proliferation has not been extensively studied.

KG-l and HL-60 clonal proliferation in vitro is inhib-

ited by prostaglandin of the E series, but not of the F

group.2’ KG-I cell growth is inhibited by dibutyryl

cyclic AMP and the extracellular agonists of this

nucleotide, but not by dibutyryl cyclic GMP and its

extracellular stimulators. These findings parallel the

response of normal human granulocyte-monocyte

progenitor cells (CFU-C). Likewise, KG-i clonal

growth is slightly inhibited by pharmacologic concen-

trations of dexamethasone (l0� M), while HL-60

cells are resistant to the glucocorticoid’s effect.29 Both

KG-I and HL-60 have high affinity (Kd = 3-4 x i0�

M) glucocorticoid receptors with a mean of 10,300

and I 5,600 3H-dexamethasone binding sites per cell,

respectively.29 These binding data are comparable to

the glucocorticoid receptor activity seen in acute

lymphocytic leukemia cells. In contrast to ALL cells,

however, no correlation was observed between the

number of glucocorticoid receptors and in vitro inhib-

ition of myelogenous leukemic cell proliferation.

Recently, it was shown that dexamethasone inhibits

the expression of Fc receptors on HL-60 cells.3#{176}

MATURATION AND CELL FUNCTION

Myeloid leukemia cells have a growth advantage

over normal cells. The growth advantage is not due to




.�-�


A

----- I

the rapid rate of proliferation of the leukemia blast

cells, as these cells usually divide more slowly than

normal cells. The leukemic cells accumulate because

of their inability to mature to functional nondividing

end cells. Since maturation and proliferation are

Fig. 3. (A) HL-60 cells at myelocyte and

metamyelocyte stage after 6 days DMSO(1 .25%) exposure. (B) KG-i cells become

large. alpha-naphthyl-butyrate-esterase-positive cells after 4 days exposure to thephorbol diester. 12-0-tetradecanoyl phorbol13-acetate (10 � M).

linked events, leukemic cell growth could be greatly

diminished ifcellular maturation could be induced.

Many of the agents that are active in causing

differentiation of the mouse erythroleukemia (Friend)

and myeloid leukemia (Ml) cells3’3’ can induce granu-





locyte maturation of the HL-60 cells, including dime-

thyl sulfoxide, butyric acid, triethylene glycol, N,N-

dimethylformamide, and N ,N ,-dimethylacetamide

(Fig. 3A).32 The mature HL-60 cells respond to

chemotaxins, phagocytose, develop complement recep-

tors, produce superoxide, and reduce NBT dye.33’34

The HL-60 cells do not have alkaline phosphatase or

lactoferrin, and do not appear to develop secondary

cytoplasmic granules.

Both HL-6035 and KG-I36 differentiate into nondi-

viding macrophage-appeaning cells when exposed to

phorbol esters (Fig. 3B). The cells from both lines

become adherent and develop long pseudopodia,

assume the morphological characteristics of macro-

phages, produce NADase, nonspecific acid esterase

and lysozyme, and develop Fc receptors and the ability

to phagocytize Candida albicans and kill Straphylo-

coccus aureus. Thus, these cell lines should be useful

in studying the mechanism of early myeloid differen-

tiation along the granulocytic and mononuclear patho-

cytic pathway.

Recent evidence suggests that some K562 sublines

may be a human erythroleukemia cell line with char-

actenistics similar to the mouse Friend erythroleu-

kemia cell Iine.’�’6’37’3’ The K562 cell membrane

glycoproteins show many similarities to erythrocytes

and, in particular, the cells synthesize glycophorin A,

which is found exclusively in human erythrocytes.’4’38

In the presence of sodium butyrate, some of the cells

become benzidine positive,’5’37 and hemoglobin can be

detected in these cells using a radioimmunoassay.’6

The K562 cells produce fetal and embryonic hemoglo-

bin when grown with 0.1 mM hemin. The K562 cell

appears to be an excellent tool for the study of human

erythroid differentiation and globin gene expression. It

seems clear, however, that there are a number of

strains of K562 and these various strains may have

different properties.

It is curious that human myeloid cell lines are so

difficult to establish when contrasted to the ease with

which lymphoid cell lines are developed. The develop-

ment of B-lymphoblast lines is clearly related to EB-

virus infection, but there also are various T- and

null-lymphoid lines available that are not obviously

virus infected. The difficulty in establishing myeloid

lines as compared to permanent lymphoid cultures

may relate to intrinsic cellular factors or requirements

for as yet unidentified growth factors. Possibly, the use

of somatic hybridization or DNA transformation

using existing myeloid cell lines will permit establish-

ment of new myeloid lines with interesting and useful

features.

The human myelogenous leukemia cell lines may

provide the framework for studies leading to a deeper

understanding of the control of differentiation in

human myeloid leukemia and, in a broader perspec-

tive, the control of normal cellular differentiation.

Future studies with these cell lines and selected van-

ants should shed new light on the cell biology of

human myeloid leukemia and perhaps lead to new

therapeutic modalities. The cells will be useful in the

development of monoclonal antibodies reactive with

myeloid leukemia cells and normal myeloid cells of

different stages of maturation. The lines and their

variants will help elucidate the interaction of CSF

with myeloid cells and provide a convenient tool for

pharmacologic and chemothenapeutic investigation.

The cells should also be of use in studies of the control

of granulocytic and macnophage differentiation. Final-

ly, it is possible that modern molecular biologic tech-

niques may permit the isolation from these cell lines of

genes controlling myeloid differentiation.

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1980 56: 344-350

HP Koeffler and DW Golde Human myeloid leukemia cell lines: a review

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