Blood, 1 September 2001, Vol. 98, No. 5, pp. 1636-1637
CORRESPONDENCE
To the editor:
Role of vitamin A deficiency in the pathogenesis of
myeloproliferative disorders
Kuwata et al's recent article1 reports that
vitamin A deficiency in mice causes a systemic expansion of myeloid
cells. Based on their findings, the authors conclude that retinoids
critically control the homeostasis of myeloid cell population in vivo
and suggest that retinoid status may have an important role in the pathogenesis of various myeloproliferative disorders (MPDs). How valid
is this suggestion?
Kuwata et al's study unequivocally demonstrates that vitamin A
deficiency causes expansion of myeloid cells, but it provides no
information as to the nature of these expansions, that is, whether they
are monoclonal or polyclonal. Myeloproliferative diseases are, by
definition, clonal disorders of hemopoietic precursor cells. If, for
instance, the vitamin A deficiency-induced myeloid proliferations were
polyclonal (and reversible), as occurs in response to a variety of
stimuli such as infections, and inflammation, the relevance of this
finding to the pathogenesis of MPDs would be questionable indeed. For
this reason, clonality studies, either by cytogenetic analysis or
molecular biologic methods to confirm monoclonal nature of the myeloid
expansions, would be imperative and should be part of any animal
experiments attempting to study the role of vitamin A in the
pathogenesis of myeloproliferative diseases.
Although their experiments were carried out in mice, Kuwata et al state
that "results obtained with this animal model are relevant to many
studies performed with human myeloid cells in culture, showing that
retinoids affect myeloid cell growth, differentiation, and
apoptosis." 1(p3355) Is there any clinical evidence to
substantiate the notion that vitamin A deficiency may contribute to
various myeloproliferative disorders in humans? Supporting evidence, if
there is any, may be obtained from 2 sources: (1) epidemiological
information that there is a high incidence of MPDs in areas where
severe vitamin A deficiency is prevalent, and (2) biochemical evidence
that serum vitamin A levels are significantly reduced in patients with MPDs.
Severe vitamin A deficiency with clinical manifestations such as
xerophthalmia and keratomalacia is highly prevalent on the Indian
subcontinent and in parts of Africa. Yet there is no obvious increase
in the incidence of MPDs in these countries, compared to the West,
where vitamin A deficiency is rare.2 Indeed, unlike in
certain solid tumors such as carcinoma of the breast and colon, where
an association between vitamin A deficiency and occurrence of these
tumors has been reported, no such association has been identified
between MPDs and vitamin A-deficiency states.2,3
A preliminary study was carried out to ascertain whether serum vitamin
A levels are reduced in patients with MPDs. Estimation of serum vitamin
A levels of 34 patients with various types of MPD [polycythemia rubra
vera (17), essential thrombocythemia (10), and chronic myeloid leukemia
(7)] was carried out by high-performance liquid chromatography (HPLC)
analysis. The normal range of serum vitamin A level is 1.1 to 2.9 µM/L. The vitamin A levels of our patient cohort ranged from 1.2 to
4.1 µM/L, with a mean of 1.9 µM/L. In other words none of the
patients with MPD in this cohort has any biochemical evidence of
vitamin A deficiency. Although the vitamin A status of these patients
was not studied prior to the onset of their illness, the observation
that their serum vitamin A levels are normal would suggest that
continued myeloproliferation is not associated with deficiency of this vitamin.
It appears that there is no documented epidemiologic or demonstrable
biochemical evidence currently available to support the notion that
vitamin A deficiency plays an important role in the pathogenesis of
MPDs as suggested by Kuwata et al. Although the role of retinoids in
the pathogenesis of acute promyelocytic leukemia (APML), which is
associated with a specific genetic defect involving retinoic acid
receptors, is well established, it is unclear as to whether vitamin A
deficiency is directly involved in the causation of these disorders in
the general population in the absence of such gene defects.
Muttuswamy Sivakumaran
Correspondence: Department of Haematology, Peterborough District
Hospital, Peterborough, United Kingdom
References
1.
Kuwata T, Wang I-M, Tamura T, et al.
Vitamin A deficiency in mice causes a systemic expansion of myeloid cells.
Blood.
2000;95:3349-3356[Abstract/Free Full Text].
2.
Boyle P, Vecchia CL, Maisonneuve P, et al.
Cancer epidemiology and prevention. In:
Peckham P,Pinedo H,Veronesi U, eds.
Oxford Textbook of Oncology. Vol 1. Oxford, England: Oxford University Press; 1995:199-273.
3.
Hunter DJ, Willett W.
Vitamin A and cancer: epidemiological evidence in humans. In:
Blomhoff R, ed.
Vitamin A in Health and Disease. New York, NY: Marcel Dekker; 1994:561-584.
Response:
Vitamin A deficiency and myeloid cell growth
First, we would like to stress that the major thrust of our
paper1 is that vitamin A deficiency causes
abnormal expansion of granulocytes in mice under controlled conditions
and that we have not claimed a direct cause-effect
relationship with specific myeloproliferative disorders (MPDs), nor
have we suggested that these observations should parallel epidemiologic
data. What we suggested is that vitamin A deficiency may be a
contributing factor for the pathogenesis of some MPDs.
Dr Sivakumaran argues that MPDs are monoclonal, but our study did
not investigate whether granulocyte expansion in vitamin A-deficient
mice was polyclonal or monoclonal. Considering the almost
100% incidence of granulocyte expansion in deficient mice and the
rapid recovery after retinoic acid repletion, we feel that the
granulocyte expansion we observed may not be monoclonal in nature, a
condition distinct from a genetic mutation resulting in selective
monoclonal growth. Indeed, it seems unlikely that vitamin A deficiency
itself causes a mutation in hematopoietic cells with high incidence,
and none has been reported in this or in other systems. Therefore,
whether this condition is polyclonal or monoclonal has not been a
critical issue, since we did not regard a genetic mutation to be a
likely mechanism for the observed expansion.
With respect to the reference to MPDs, we had in mind chronic
myelogenous leukemia (CML) and chronic neutrophilic leukemia (CNL), for
which vitamin A deficiency may have a contributing role in the disease
processes. We are not suggesting that systemic vitamin A deficiency has
a significant role in the induction of MPDs, and we are not aware of
any epidemiologic data to support this notion, just as there are no
data suggesting that systemic vitamin A deficiency contributes to lung
or breast or any other type of neoplastic disease in the absence of a
mutational event. But intestinal2 and liver3
tumors or breast adenocarcinoma-derived cells,4 as well as
head and neck cancer and skin cancer cells5 all show low
retinyl ester levels and/or reduced ability to synthesize retinyl esters with respect to normal tissue. It is possible that some
of these tumors either are derived from the expansion of vitamin A-
depleted cells in the presence of a mutational event, as we have
suggested,6 or have acquired the vitamin A-deficient status as a result of a genetic mutation in one of the key retinoid signaling genes. Further, vitamin A deficiency may not occur
systemically but may be generated locally because of chronic exposure
to carcinogens, cytokines, and so forth. For instance, the lung tumor
phenotype of squamous cell carcinoma may be due to mutation events
operating on the lung epithelium rendered squamous metaplastic by
chronic exposure to cigarette smoke and/or vitamin A
deficiency.7 This localized deficiency may not be
reflected at the systemic level under normal conditions of vitamin
A nutriture.
Finally, we would like to mention here that our intention was not to
link vitamin A deficiency with specific MPDs, but rather to suggest a
potential role of vitamin A in the more general abnormalities in
myeloid cell growth and survival, beyond the narrow hematologic definition of MPD.
Luigi M. De Luca and Keiko Ozato
Correspondence: Keiko Ozato, Laboratory of Molecular Growth
Regulation, National Institute of Child Health and Human Development,
National Institutes of Health, Bethesda, MD 20892-2753
References
1.
Kuwata T, Wang I-M, Tamura T, et al.
Vitamin A deficiency in mice causes a systemic expansion of myeloid cells.
Blood.
2000;95:3349-3356.
2.
Sundaresan PR, De Luca LM.
Vitamin A contents of rat intestinal epithelium and jejunal mucinous adenocarcinoma.
J Natl Cancer Inst.
1977;58:1643-1645.
3.
De Luca LM, Brugh M, Silverman-Jones C.
Retinyl palmitate, retinyl phosphate and dolichyl phosphate of postnuclear membrane fraction from hepatomas, host liver, and regenerating liver: marginal vitamin A status of hepatoma tissue.
Cancer Res.
1984;44:224-232[Abstract/Free Full Text].
4.
Andreola F, Giandomenico V, Spero R, De Luca LM.
Expression of a smaller lecithin:retinol acyl transferase (LRAT) transcript and reduced retinol esterification in MCF-7 cells.
Biochem Biophys Res Commun.
2000;279:920-924[CrossRef][Medline]
[Order article via Infotrieve].
5.
Guo X, Gudas LJ.
Metabolism of all-trans retinol in normal human cell strains and squamous cell carcinoma (SCC) lines from the oral cavity and skin: reduced esterification of retinol in SCC lines.
Cancer Res.
1998;58:166-176[Abstract/Free Full Text].
6.
De Luca LM.
The concept of nutritional exotrophism in carcinogenesis.
Clin. Nutr.
1989;8:187-191[Medline]
[Order article via Infotrieve].
7.
Lancillotti F, Darwiche N, Celli G, De Luca LM.
Retinoid status and the control of keratin expression and adhesion during the histogenesis of squamous metaplasia of tracheal epithelium.
Cancer Res.
1992;52:6144-6152[Abstract/Free Full Text].
