Blood, 15 August 2001, Vol. 98, No. 4, pp. 1272-1273
CORRESPONDENCE
To the editor:
Misleading information about ALIP and VEGF in
myelodysplasia
The study by Bellamy et al1 has numerous critical
limitations. First, the authors incorrectly assume that abnormal
localization of immature precursors (ALIPs) can be identified in the
bone marrow clot section, which has no bony trabeculae. It should be
pointed out that ALIPs are collections of immature myeloid precursors in the central, intertrabecular region of the bone marrow trephine biopsy section.2,3 Moreover, this is a feature of
microarchitecture disorganization in the bone marrow biopsy sections in
myelodysplastic syndromes (MDSs), which also show disorganized
erythroid and megakaryocytic precursors in the trabecular
region.3,4 In a normal human bone marrow biopsy, myeloid
precursors are near the trabecular region, and erythroid and
megakaryocytic precursors are in the intertrabecular
region.5 This physiologic cell distribution may be
reversed in the bone marrow biopsy of cases with MDS.4 The
data presented by Bellamy et al1 show only myeloid and monocytoid blasts in a clot section without bony trabeculae, which is
typical of blasts seen in a bone marrow aspirate. Moreover, it is
reported that most myeloid blasts and myeloid leukemia cell lines
express vascular endothelial growth factors (VEGFs) and their
receptors.6,7 This simply indicates that, like acute myeloid leukemia blasts, immature myeloid cells in MDS do express VEGF
and this is not specific to displaced/ectopic blasts or ALIP.
Second, the authors show absence of VEGF in a healthy human bone marrow
clot section, but their data highlight only the absence of VEGF in
mature myeloid cells (neutrophils). Like normal bone marrow, Figure 4 in Bellamy et al clearly demonstrates absence of VEGF in all mature
myeloid cells in cases with MDS. Therefore, we do not know whether
healthy human bone marrow blasts differ from "dislocated myeloid
precursors" (Bellamy et al1), and they do not have
autocrine or paracrine promotion by VEGF.
Third, their data show that cases with refractory anemia (RA, or
low-risk MDS) were 100% (8 of 8) positive for VEGF, and only 72% (16 of 22) of cases with refractory anemia with excess of blasts (RAEB) and
RAEB in transformation (RAEBt) show positivity for VEGF. According to
our experience3,4 and that of others,2 only
30% of cases with RA show presence of ALIP and more than 95% of cases
with RAEB/RAEBt (high-risk MDS) do have ALIP in their bone marrow
biopsies. Bellamy et al1 do not clarify how many RA and
RAEB/RAEBt cases were with ALIP and without ALIP, why RAEB/RAEBt cases
with ALIP do not demonstrate positivity for VEGF, and what is the
explanation for VEGF positivity in RA cases without ALIP.
Fourth, the authors do not mention anything about the international
prognostic scoring system (IPSS) in MDS.8 This scoring system is used by most physicians to make a therapeutic decision in cases with MDS. It will be interesting to know about any
correlation between VEGF expression and IPSS risk categories.
Finally, most investigators will agree that lymph-node fine-needle
aspirates do not give enough information about lymph node architecture.
Likewise, bone marrow clot sections are not suitable to start assuming
about architectural disorganization in MDS. To get the full picture
about ALIP in MDS and the autocrine or paracrine promotion by VEGF or
other growth factors, authors should justify their conclusions on the
basis of bone marrow biopsy examinations.
Manzoor H. Mangi
Correspondence: Manzoor H. Mangi, Department of Haematology, The
Royal London Hospital, Whitechapel, London E1 1BB, England, United
Kingdom; m.h.mangi{at}mds.qmw.ac.uk
References
1.
Bellamy WT, Richter L, Sirjani D, et al.
VEGF is an autocrine promotor of abnormal localized immature myeloid precursors and leukemic progenitor formation in myelodysplastic syndromes.
Blood.
2001;97:1427-1434[Abstract/Free Full Text].
2.
Tricot G, De Wolf-Peeters C, Hendrickx B, Verwilghen RL.
Histological findings in myelodysplastic syndromes and comparison with bone marrow smears.
Br J Haematol.
1984;57:423-430[Medline]
[Order article via Infotrieve].
3.
Mangi MH, Salisbury JR, Mufti GJ.
Abnormal localization of immature precursors (ALIP) in the bone marrow of myelodysplastic syndromes: current state of knowledge and future directions.
Leuk Res.
1991;15:627-639[Medline]
[Order article via Infotrieve].
4.
Mangi MH, Mufti GJ.
Primary myelodysplastic syndromes: diagnostic and prognostic significance of immunohistochemical assessment of bone marrow biopsies.
Blood.
1992;79:198-2025[Abstract/Free Full Text].
5.
Schafer HE.
Cytology and histopathology of normal human bone marrow. In:
Lennert K,Hubner K, eds.
Pathology of Bone Marrow. Stuttgart, Germany: Verlag; 1984:33-53.
6.
Bellamy WT, Richter L, Frutiger Y, Grogan TM.
Expression of vascular endothelial growth factor (VEGF) and its receptors in hematopoietic malignancies.
Cancer Res.
1999;59:728-733[Abstract/Free Full Text].
7.
Mangi MH, Newland AC.
Angiogenesis and angiogeneic mediators in haematological malignancies.
Br J Haematol.
2000;111:43-51[CrossRef][Medline]
[Order article via Infotrieve].
8.
Greenberg P, Cox C, LeBeau M, et al.
International scoring system for evaluating prognosis in myelodysplastic syndromes.
Blood.
1997;898:2079-2088.
Response:
Expression of VEGF in myelodysplasia
Dr Mangi interprets our data as indicating that the means by
which we diagnose ALIP was based solely on findings derived from bone
marrow clot sections.1 The definition of ALIP as
originally proposed by Tricot et al2,3 resides upon
resolving the spatial relationship between myeloblast clusters to bone
trabeculae within trephine biopsies, as we described in
"Discussion."1(pp1432-1433) Indeed, we stress that the
displacement of myeloid precursor clusters from their paratrabecular
locale represents an adverse prognostic feature in MDS that is
associated with an imminent risk for leukemic transformation. We do
not, however, base a diagnosis of ALIP on bone marrow clot sections
alone. All myeloblast clusters identified in marrow clot sections were
confirmed by trephine biopsy prior to immunohistochemical staining. Our
use of bone marrow clot sections to examine VEGF and receptor
expression was predicated on the superior staining characteristics of
bone marrow clot sections as compared to cores under the conditions
used for staining in this study. Nevertheless, Mangi's letter now
prompts us to include a figure showing VEGF expression in ALIP in a
bone marrow trephine biopsy. Although the level of staining is not as
optimal as that observed in the clot sections provided in the original
manuscript, VEGF expression is clearly demonstrated (Figure 1).
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| Figure 1.
Expression of VEGF in ALIP.
Bone marrow trephine biopsy from a patient with myelodysplastic
syndrome demonstrating expression of VEGF in myeloblast clusters
(arrows). T indicates trabecular bone. Panel A, 250 × magnification;
panel B, 1000 × magnification.
|
|
Dr Mangi incorrectly states that we conclude that the VEGF/receptor
profile is specific to ALIP. We do not state that the observed staining
characteristics are specific to ALIP and, indeed, a similar pattern is
observed in AML, an observation that we report from our own data in the
manuscript. But acquisition of the VEGF autocrine responsive phenotype
may represent an early event in AML evolution that might also
facilitate homotypic myeloblast adhesion.
Although we report the characteristic staining pattern for
VEGF/receptor in isolated myelomonocytic precursors in 8 of 8 patients with refractory anemia, we do not describe ALIP in this low-risk FAB
category, as stated by Dr Mangi. We fully agree with Dr Mangi that the
International Prognostic Scoring System (IPSS) in MDS is a useful
scoring system based upon clinical and pathologic features at disease
presentation.4 Our series of patients was not restricted
to bone marrow specimens obtained at diagnosis and includes patients
with proliferative chronic myelomonocytic leukemia (CMML),
which are excluded from the IPSS.
An important aspect of our study overlooked by Dr Mangi is that, while
we and others have demonstrated the expression of VEGF in hematopoietic
malignancies,5-8 this is one of the first reports to
characterize the functional relevance as it relates to potential autocrine stimulation of tumor growth and survival. Such translational investigations are critical to the development of novel therapies targeting the VEGF-receptor axis and to thereby offer the potential to
impact leukemia progenitor growth and development.
William T. Bellamy, Thomas M. Grogan, and Alan F. List
Correspondence: William T. Bellamy, Department of Pathology,
University of Arizona, 1501 N Campbell Ave, Tucson, AZ 85724;
wbellamy{at}u.arizona.edu
References
1.
Bellamy WT, Richter L, Sirjani D, et al.
Vascular endothelial cell growth factor (VEGF) is an autocrine promoter of abnormal localized immature myeloid precursors (ALIP) and leukemia progenitor formation in myelodysplastic syndromes.
Blood.
2001;97:1427-1434.
2.
Tricot G, De Wolf-Peeters C, Hendrickx B, Verwilghen RL.
Histological findings in myelodysplastic syndromes and comparison with bone marrow smears.
Br J Haematol.
1984;57:423-430.
3.
Tricot G, Vlientinck R, Boogaerts MA, et al.
Prognostic factors in the myelodysplastic syndromes: importance of initial data on peripheral blood counts, bone marrow cytology, trephine biopsy and chromosomal analysis.
Br J Haematol.
1985;60:19-32[Medline]
[Order article via Infotrieve].
4.
Greenberg P, Cox C, LeBeau M, et al.
International scoring system for evaluation prognosis in myelodysplastic syndromes.
Blood.
1997;89:2079-2088[Abstract/Free Full Text].
5.
Bellamy WT, Richter L, Frutiger Y, Grogan TM.
Expression of vascular endothelial growth factor (VEGF) and its receptors in hematopoietic malignancies.
Cancer Res.
1999;59:728-733.
6.
Pruneri G, Bertolini F, Soligo D, et al.
Angiogenesis in myelodysplastic syndromes.
Br J Cancer.
1999;81:1398-1401[CrossRef][Medline]
[Order article via Infotrieve].
7.
Fiedler W, Graeven U, Ergun S, et al.
Vascular endothelial growth factor, a possible paracrine growth factor in human acute myeloid leukemia.
Blood.
1997;89:1870-1875[Abstract/Free Full Text].
8.
Hussong JW, Rodgers GM, Sami PJ.
Evidence of increased angiogenesis in patients with acute myeloid leukemia.
Blood.
2000;95:309-313[Abstract/Free Full Text].
