Adv Cancer Res 1998;. 72: 141â196 ... chromosomal abnormalities have been identified in pediatric B-cell ..... Genes Chromosomes Cancer 2001; 30: 407â409.
Correspondence
representative of MM patients. Bone marrow mononuclear cells were isolated by Ficoll–Hypaque sedimentation and extracted DNA was modified for MSP by bisulfite using the CpGenomeTM DNA Modification Kit (Intergen, Purchase, USA). SOCS-1 gene promoter regions were amplified with DNA methylated and unmethylated specific primers as previously described.5 A total of 51 samples of MM bone marrow cells were analyzed by MSP. Selective methylation of SOCS-1 gene was found in 38/51 patients (74.5%). No correlation could be made between SOCS-1 gene methylation and gender, age, isotype, level of M-component, stage of the disease, serum levels of albumin, creatinin, calcium, b2-microglobulin, LDH, C-reactive protein, or response to treatment. Overall survival was not significantly different between patients with methylated and unmethylated SOCS-1 gene (P ¼ 0.58), median survival being estimated at 27.1 months (95% CI, 14.4–39.8) and 23.1 months (95% CI, 17.3–28.9), respectively (Figure 1). Methylation of SOCS-1 gene is frequent in MM, occurring at frequencies of 75% in our series. It may represent an important epigenetic event in the pathogenesis of MM. However, SOCS-1 gene methylation does not seem to influence the clinical outcome of MM patients.
S Depil1,2 A Saudemont1,2 B Quesnel1,2
1679 1
Unite´ INSERM 524, IRCL, Lille, France; 2 Service des Maladies du Sang, CHU de Lille, Lille, France
References 1 Klein B, Zhang XG, Lu ZY, Bataille R. Interleukin-6 in human multiple myeloma. Blood 1995; 85: 863–872. 2 Heinrich PC, Behrmann I, Muller-Newen G, Schaper F, Graeve L. Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem J 1998; 334 (Part 2): 297–314. 3 Nicola NA, Greenhalgh CJ. The suppressors of cytokine signalling (SOCS) proteins: important feedback inhibitors of cytokine action. Exp Hematol 2000; 28: 1105–1112. 4 Baylin SB, Herman JG, Graff JR, Vertino PM, Issa JP. Alterations in DNA methylation: a fundamental aspect of neoplasia. Adv Cancer Res 1998; 72: 141–196. 5 Yoshikawa H, Matsubara K, Qian GS, Jackson P, Groopman JD, Manning JE et al. SOCS-1, a negative regulator of the JAK/STAT pathway, is silenced by methylation in human hepatocellular carcinoma and shows growth-suppression activity. Nat Genet 2001; 28: 29–35. 6 Galm O, Yoshikawa H, Esteller M, Osieka R, Herman JG. SOCS-1, a negative regulator of cytokine signalling, is frequently silenced by methylation in multiple myeloma. Blood 2003; 101: 2784–2788.
Amplification of band q22 of chromosome 21, including AML1, in older children with acute lymphoblastic leukemia: an emerging molecular cytogenetic subgroup Leukemia (2003) 17, 1679–1682. doi:10.1038/sj.leu.2403000
TO THE EDITOR Acute lymphoblastic leukemia (ALL) is a heterogeneous disease at the chromosomal and molecular levels. Several subgroups of chromosomal abnormalities have been identified in pediatric B-cell precursor ALL: hyperdiploidy in which more than 50 chromosomes are present, near haploidy, and translocations t(12;21), t(1;19), t(9;22), and t(4;11) or other 11q23 abnormalities. With the development of specific fluorescence in situ hybridization (FISH) probes to evaluate metaphase chromosomes or interphase nuclei, chromosomal abnormalities can now be detected when leukemic cells have cryptic alterations or a karyotype that cannot be determined. The frequent use of TEL-AML1 probes to evaluate the cryptic t(12;21) have identified isolated cases in which the AML1 gene is amplified or over-represented.1–5 This chromosomal abnormality is most often detected by conventional cytogenetic methods as a tandem duplication of chromosome band 21q22 or as marker chromosomes of unknown origin.1-5 However, in B-cell precursor ALL, various numerical and structural abnormalities of chromosome 21 can lead to multiple copies of AML1. Among the abnormalities are trisomy or tetrasomy 21 (which can be the sole abnormality or associated with high hyperdiploidy 450 chromosomes), and isochromosomes 21q or ider(21q)t(12;21). Therefore, more stringent molecular methods of detection are needed to specifically identify AML1 amplification. Before we attempted to confirm that amplification of band 21q22, including AML1, is characteristic of an emerging ALL subtype, we developed a FISH-based inclusion criteria for detection of AML1 amplification/over-representation by FISH. These consisted of detection of four or more AML1 signals in interphase nuclei, and the colocalization of three or more signals on the same metaphase
Correspondence: Dr SD Raynaud, Unite´ de Cytoge´ne´tique des He´mopathies Malignes, Hoˆpital de l’Archet, BP79, Nice Cedex 06202, France; Fax: +33 4 920 364 65 Received 14 January 2003; accepted 28 March 2003
chromosome; when no mitotic cells were obtained, the presence of an AML1 amplification was considered to have occurred if FISH resulted in five or more AML1 signals in interphase nuclei. It is generally accepted that up to four to five copies of a gene the term of over-representation should be prefered, and above that number amplification can be used. On the basis of these inclusion criteria, we report here 16 pediatric patients with B-cell precursor ALL and amplification/over-representation of band q22 including AML1 (Table 1). Patients were referred to pediatric centers in France (Centre Hospitalier Universitaire CHU Brest; CHU Nantes; CHU Nice, France; CHU Saint-Louis, Paris, France), St Jude Children’s Research Hospital (Memphis, TN, USA), Mount Sinai Medical Center (New York, NY, USA), or Chaim Sheba Medical Center (Tel-Hashomer, Israel). The diagnosis of B-cell precursor ALL was based on the morphology criteria of the French–American–British Group, the expression of B-cell-associated antigens CD19, CD22, CD10, and the absence of membrane immunoglobulins. Cytogenetic analyses were performed on mitotic bone marrow or blood cells according to standard procedures. Chromosomes were trypsin-Wright or RHG banded. Karyotyping was carried out according to the guidelines of the International System for Human Cytogenetic Nomenclature (ISCN 1995). Patients were enrolled in one of the following frontline clinical trials: protocols FRALLE 1993 and 2000, EORTC 58981, St Jude protocols Total XII and XIII, and Berlin–Frankfurt–Munster (BFM) protocols 1995 and 1998. The studies were approved by the appropriate ethic committees of each institution, and informed consent was obtained from patients or guardians. In five of the seven cytogenetic laboratories involved in this study, the detection by FISH of the t(12;21) was performed prospectively for the last 2 years on all newly diagnosed B-cell ALL cases. In the remaining two centers, FISH using a probe specific to the TEL-AML1 fusion gene is usually performed to confirm positive PCR results, or when chromosome 12p or chromosome 21 abnormalities are suspected. The LSI TEL-AML1 ES dual-color translocation probe (Vysis, Downer’s Grove, IL, USA and Adgenix, Voisin-Le-Bretonneux, France) was used by all laboratories. This probe is a mixture of the Leukemia
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1680 Table 1 Study (references)
Pediatric B-cell precursor ALL cases with AML1 amplification (present study and published cases) WBC 109/l (blast %)
Case No
Sex/Age
1 2 3* 4* 5 6 7
F/11 F/13 M/17 F/19 M/14 M/12 F/13
PS (1) (2) (2) (3) (7) (8)
8 #1 #3 #1 #1 #40 #44
F/15 M/12 F/11 M/15 F/10 F/15 M/13
9.9 (64) 4.3 (NA) NA 4.3 (35) 1.4 (4) NA 7.6 (NA)
PS/(5) PS/(10)
9* 10*
F/8 F/12
0.9 (1.5) 7.1 (3)
PS
11
F/13
6.6 (55)
(3) (1)
#2 #2
M/11 F/5.6
5.9 (0) 26.3 (NA)
PS
12
M/5
7.2 (NA)
PS (2)
13 #2
F/6 M/6
3,1 (12) 4.9 (61)
PS (9) (8) (7) (7)
14 #1 #64 #38 #39
M/11 F/15 M/14 M/2.9 F /3.4
NA NA 14.5 (NA) NA NA
PS PS (8)
15 16 #65
F/11 M/7 F/8
1.6 (4) NA 2.0 (NA)
PS PS PS/(4) PS/(4) PS PS PS
18 2.8 1.0 10.1 2.2 15.1 3.8
(60) (50) (50) (72) (22) (70) (1)
Karyotypes
AML1 signals by FISH (% of abnormal IN)
Follow-up CR
>10 (60) 5–10 (92) 8 (98) 6–8 (99) 5–7 (72) 5–7 (98) 5 (96.5)
20m+ 18m+ 19m+ 21m+ 23m, 2m+ 2m+ 61, 56, 10m+
4 (68) 10–15 5 4–5 4–5 >4 4
86m+ NA 64m 32m+ 14m+ 13m+ 18m+
510 (85) 5 (66)
9m+ 48m+
5 (37)
10m+
6 6
7m+ NA
5–10 (30)
24m+
4–10 (93) 4–5
5m+ Na
Normal karyotype 46,XY [30] 46,XX [20] 46,XY 46,XY 46,XY
3–10 (NA) 15–20 (70) 6–15 4–5 >4
NA Relapse 48m+ 14m+ 8m+
Karyotype failure Failure Failure Failure
>10 (97) 4–10 (NA) 6–15
75m+ NA 52m+
Pseudodiploid 46,XX,del(8)(q?),+13,-19,add(21)(p) [5] 46,XX,-21,+mar [9] /46,XX [2] 46,XY,add(1)(q25),add(21)(q21) [6] /46,XY [14] 46,XX,del(7)(p14p21),-21,+mar [10] /46,XX [2] 46,XY,inv(7)(p?15q?21),-21,+mar [2] /46,XY [4] 46,XY,-21,+mar [8] 46,XX,del(7)(q22q35),del(11)(p12),add(21)(p11.2) [9] /46,XX [5] 46,XX,trp(21)(q11.2q22) [13] /46,XX [7] 46,XY,del(18)(p11),der(21) 46,XX,-21,+mar 46,X,-Y,add(21)(q22),+mar1 [8] /46,XY [12] 46,XX,der(21) [2] 46,XX,add(1)(p?),del(6)(q25) 46,XY,i(9)(q10),-16,+mar (trp 21q using SKY) Low hyperdiploid 47,XX,+X,del(21)(q22),der(21) [12] /46,XX [4] 48,XX,+X,+10,del(11)(q23),qdp(21)(q11q22) [13] /46,XX [7] 47,XX,?add(4)(q31),del(7)(q3?2),i(21),+mar [5] /46,XX [10] 47,X,+X,inv(Y)(p11.2q12),+10,-20,der(21) [20] 48,XX,-20,+der(21),+2mar High hyperdiploid >50 chromosomes 56,XY,+X,+Y,+6,+10,+14,+17,-19,+21, +22,+mar1,+mar2, +mar3 [5] /46,XY [18] 54,XX,+X,+6,+9,+14,+17,+18,+2mar [12] 53,XY,+X,+Y,inv(3),add(4),+9,+17,+21,+21, +add(21)(q22)
Notes: PS, cases from the present study; *, cases partially described in Penther et al,4 Morel et al5 and Mathew et al;10 IN, interphase nuclei CR m+, months of ongoing complete remission; NA, not available. The chromosomes that most likely hybridized with AML1 probe were written in bold.
LSI TEL probe labeled with Spectrum Green and the AML1 probe labeled with Spectrum Orange. The approximately 500 kb AML1 probe spans the entire AML1 gene and contains genomic DNA centromeric to this gene, which is located at 21q22. The probe was used according to the manufacturer’s recommendations. Briefly, slides were denatured at 751C for 2 min; probes were denatured at the same temperature for 5 minutes. Subsequently, the two were hybridized overnight at 371C. Hybridization signals were evaluated by using DAPI/FITC/rhodamine triple-band pass filter sets. According to our FISH inclusion criteria, we found that the leukemic cells from the 16 pediatric patients with newly diagnosed B-cell precursor ALL had multiple copies of band q22 including AML1. The AML1 copy number ranged from four to more than 10 per interphase nuclei or metaphase chromosomes (Table 1 and Figure 1). Multiple 21q22 and AML1 signals were clustered in an area within the interphase nuclei in most cases (Figure 1, panels A– C), and were consistently located on the same metaphase chromosome. All cases in this study had high percentages of cells with the AML1 amplification; in fact, almost all of the leukemic cells Leukemia
contained this amplification, a finding consistent with the hypothesis that this is a major oncogenic event. Two signals specific for the TEL probe were observed in all cases. When conventional cytogenetic findings were evaluated, we identified four ploidy patterns (Table 1): pseudodiploid (n ¼ 8), low hyperdiploid (from 47 to p50 chromosomes) (n ¼ 3), high hyperdiploid 450 chromosomes (n ¼ 2), and diploid (n ¼ 1). No karyotype was determined for two additional cases because of the absence of mitotic cells; no DNA index was available for these patients. All patients in the pseudodiploid and low hyperdiploid groups had marker chromosomes, numerical or structural abnormalities of chromosome 21 such as add(21q), del(21q), trp(21q), qdq(21q), or both marker chromosomes and chromosome 21 abnormalities. FISH with whole-chromosome painting probes showed that these marker chromosomes originated from chromosome 21 (data not shown). FISH using the locus-specific AML1 probe resulted in the appearance of several signals on a single chromosome (Figure 1, panel d). Conventional cytogenetics revealed various structural or numerical chromosome abnormalities
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1681
a
b
c
d
e mar1 (AML1++)
mar(AML1++)
mar1 (AML1++)
Figure 1 FISH analyses using AML1 (red signal) and TEL (green signal) probes. AML1 amplification was detected on interphase nuclei (a–c) and metaphase chromosomes (d–e). Different patterns according to karyotypes are shown: pseudodiploid (case 2, a and d), hyperdiploid (case 13, b and e), and karyotype failure (case 16, c). Arrows show chromosomes with AML1 extra signals. Note that AML1 extra signals are clustered in one area within interphase nuclei.
with pseudodiploidy or low hyperdiploidy. The clinical and biological features of these eight patients were consistent with our findings, including older age (median, 11.5 years) and low WBC counts (median, 4.3 103/ml) (Table 1). The similarity in the characteristics of these cases suggests that amplification of 21q22, including AML1, within pseudodiploid or low hyperdiploid leukemic cells represents an emerging subtype of B-cell precursor ALL, potentially distinct from the subtypes characterized by the t(12;21) and other recurrent chromosome abnormalities. A systematic prospective screening of AML1 amplification in ongoing ALL clinical trials is now necessary to determine the frequency and the prognostic value of this cytogenetic abnormality. It is unknown what genes are the targets of the amplification process. Besides AML1 there is evidence that 21q22.13-22.2 and subtelomeric 21q band are also amplified (V Najfeld, data not shown), and other gene(s) at 21q22 might be oncogenic target(s) activated by amplification. Genomic and expression analyses should help to elucidate the oncogenic mechanisms associated with multiple copies of 21q22 and AML1 amplification in this newly recognized molecular cytogenetic subgroup of ALL.
Acknowledgements were also present in most cases. Among the patients in the high hyperdiploidy group, at least two did not have tetrasomy 21 as indicated by conventional cytogenetics. This finding suggests that the 21q22 amplification could be a functional equivalent of tetrasomy 21 in high hyperdiploid ALL. Moreover, the marker chromosome in which AML1 was amplified was duplicated in patient 13 (Figure 1, panel b). However, caution should be taken in this interpretation as possible asymmetry of replication and the presence of twin/double spots cannot be ruled out in some of these cases. The interpretation of cases with normal karyotypes and 21q22 amplification is equivocal; probably the leukemic cells are not dividing; alternatively the amplification could be cryptic. In all cases, conventional cytogenetics, FISH and/or molecular analyses did not detect recurrent translocations, including the t(12;21), t(9;22), and t(4;11), in association with AML1 amplification. When the major clinical and biological features of the pediatric patients with ALL and multiple copies of 21q22 including AML1 were analyzed, particular features appeared to be associated with the pseudodiploid and low hyperdiploid groups. Within these groups (n ¼ 11), the median age was 13 years (range, 8–19); in contrast, the two patients in the high hyperdiploid group were only 5 and 6 years old. The peripheral white blood cells (WBCs) counts at diagnosis were low (median, 6.6 103/ml; range, 0.9–18). In comparison, the median age of patients with B-cell precursor ALL in the FRALLE 93 trial (n ¼ 1195) was 4.7 years (range, 0.1 to 19 years) and the median WBC count was 9.5 103/ml (range, 0.3– 1350).6 Immunological analysis using a standard antibody panel revealed common CD10-positive B-cell precursor phenotype in all cases. Furthermore, six cases were early pre-B (Cm, sIgm), five were pre-B (Cm+, sIgm) and one was transitional (Cm+, sIgm+). Some genetically distinct subgroups of precursor-B ALL are closely associated with characteristic but not unique immunophenotypes. For example, t(1;19) with CD19+/CD10+/CD34, pre-B ALL phenotype; t(12;21) with CD19+/CD10+/CD9dim/CD20dim and either CD13+ or CD33+; and t(4;11)(q21;q23) with CD19+/CD10-/ CD15+. We observed no particular association of 21q22 amplification with immunophenotype. Remission was achieved in the 14 patients for whom clinical records were available. The median follow-up period was 21 months (range, 0.5 to 127). Although two of the patients relapsed, one is in second remission, and the other is in third remission. Using our FISH criteria, we evaluated cases from the literature and identified 14 additional pediatric cases with ALL and amplification or over-representation of 21q22, including eight cases
This study was supported in part by grants from the National Institutes of Health (CA 21765), the American Lebanese Syrian Associated Charities, and the French Department of Health (Programme de Soutien aux Innovations Diagnostiques et The´rapeutiques Couˆteuses). We thank Dr JC Jones (St Jude Children’s Research Hospital) for critical reading of the paper.
J Soulier1 L Trakhtenbrot2 V Najfeld3 JM Lipton3 S Mathew4 H Avet-Loiseau5 M De Braekeleer6 S Salem7 A Baruchel1 SC Raimondi8 SD Raynaud7
1
Centre Hospitalier Universitaire (CHU) Saint Louis, AP-HP, Paris, France; 2 The Chaim Sheba Medical Center, Tel-Hashomer, Israel; 3 The Mount Sinai Medical Center, New York, NY, USA; 4 New York Presbyterian Hospital-Cornell Campus Cornell University Weill Medical College, New York, NY, USA; 5 CHU Nantes, France; 6 CHU Brest, France; 7 CHU Nice, France; 8 Jude Children’s Research Hospital, Memphis, TN, USA
References 1 Niini T, Kanerva J, Vettenranta K, Saarinen-Pihkala UM, Knuutila S. AML1 gene amplification: a novel finding in childhood acute lymphoblastic leukemia. Haematologica 2000; 85: 362–366. 2 Busson-Le Coniat M, Nguyen Khac F, Daniel MT, Bernard OA, Berger R. Chromosome 21 abnormalities with AML1 amplification in acute lymphoblastic leukemia. Genes Chromosomes Cancer 2001; 32: 244– 249. 3 Dal Cin P, Atkins L, Ford C, Ariyanayagam S, Armstrong SA, George R et al. Amplification of AML1 in childhood acute lymphoblastic leukemias. Genes Chromosomes Cancer 2001; 30: 407–409. 4 Penther D, Preudhomme C, Talmant P, Roumier C, Godon A, Mechinaud F et al. Amplification of AML1 gene is present in childhood acute lymphoblastic leukemia but not in adult, and is not associated with AML1 gene mutation. Leukemia 2002; 16: 1131–1134. 5 Morel F, Herry A, Le Bris MJ, Douet-Guilbert N, Le Calvez G, Marion V et al. AML1 amplification in a case of childhood acute lymphoblastic leukemia. Cancer Genet Cytogenet 2002; 137: 142–145. 6 Donadieu J, Auclerc MF, Baruchel A, Perel Y, Bordigoni P, LandmanParker J et al. French Acute Lymphoblastic Leukaemia Group (FRALLE). Prognostic study of continuous variables (white blood cell count, peripheral blast cell count, haemoglobin level, platelet count and age) in Leukemia
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1682 childhood acute lymphoblastic leukaemia. Br J Cancer 2000; 83: 1617– 1622. 7 Martinez-Ramirez A, Urioste M, Contra T, Cantalejo A, Tavares A, Portero JA et al. Fluorescence in situ hybridization study of TEL/AML1 fusion and other abnormalities involving TEL and AML1 genes. Correlation with cytogenetic findings and prognostic value in children with acute lymphocytic leukemia. Haematologica 2001; 86: 1245– 1253. 8 Nordgren A, Heyman M, Sahlen S, Schoumans J, Soderhall S, Nordenskjold M et al. Spectral karyotyping and interphase FISH reveal
abnormalities not detected by conventional G-banding. Implications for treatment stratification of childhood acute lymphoblastic leukaemia: detailed analysis of 70 cases. Eur J Haematol 2002; 68: 31–41. 9 Sun G, Qin N, Sun N, Close P, Wang S, Yang X et al. Intrachromosomal amplification of AML1 gene in a pre-B-ALL in relapse detected predominantly in interphase cells by FISH. Blood 2001; 98(Suppl): 448. 10 Mathew S, Rao PH, Dalton J, Downing JR, Raimondi SC. Multicolor spectral karyotyping identifies novel translocations in childhood acute lymphoblastic leukemia. Leukemia 2001; 15: 468–472.
Classification of mature T-cell leukemias Leukemia (2003) 17, 1682–1683. doi:10.1038/sj.leu.2403003
TO THE EDITOR We agree with Kussick et al1 that not every case of T-cell leukemia is easily classifiable. However, the only way forward in establishing the correct diagnosis and improving the WHO classification is to be able to define new disease entities. Currently, there are no data in the literature, nor in their letter, to support the view that there is a Tcell leukemia that should be classified as T-cell chronic lymphocytic leukemia (T-CLL). Historically, the term ‘T-CLL’ was first used by Brouet et al 2 in 1975, when they described patients who would now be considered largely to be part of T-cell large granular lymphocytic (T-LGL) leukemia and a few cases that we now call T-prolymphocytic leukemia (T-PLL). A large number of subsequent reports and data emerging from the literature have allowed us to separate T-LGL leukemia from T-PLL.3,4 Since then, there has been no clear evidence that a third entity, T-CLL, as proposed by Kussick et al,1 indeed exists. We recognize that in T-PLL there is a degree of morphological heterogeneity, which is already considered in the WHO classification5 and in our experience.3–6 Therefore, the classification of T-cell malignancies should not be based purely on the morphological criteria but substantiated by the underlying molecular/genetic features as well as clinical manifestations. Not all T-PLL cases have circulating cells with the morphology of prolymphocytes as in the classic 1974 description by Galton, which is more applicable to B-cell PLL. Although the term ‘prolymphocyte’ may not be ideal to use in this condition, it has been retained for historical reasons and indeed, provided everybody understands the disease behavior and what this term defines, this should not be an issue. On reviewing the representative case #1 reported by Kussick et al,1 it is likely that this represents an example of small-cell variant T-PLL, as defined by the WHO classification and as seen by us in many patients;3–6 the cells in the black and white illustration appear typical, with cytoplasmic blebs, although a nucleolus is not prominent, a feature that is common in the small-cell T-PLL variant. The phenotype CD4+, CD7+, CD8 would fit very well with T-PLL. Unfortunately, the key investigation, chromosome analysis and/or overexpression of TCL-1 or mutational analysis for ATM – features also characteristic of T-PLL,7–9 – have not been performed. A second case in which no details are given does not add weight to their argument. We would also disagree that there is a conflict between the REAL and the WHO classifications.5,10 The REAL was an attempt to start grouping cases into disease entities; there was no clear separation of cases within the mature T-cell leukemias, but since that timeextensive work has been carried out and a consensus reached Correspondence: Dr E Matutes, Academic Department of Haematology & Cytogenetics, The Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK; Fax: +44 20 7351 6420 Received 14 March 2003; accepted 26 March 2003 Leukemia
between pathologists and clinicians. The very high WBC of case #1, 500 109/l, fits with the aggressive nature of the disease. We are not given any details of follow-up but, in our experience, without appropriate treatment, the median survival of T-PLL is 7 months.3 We feel that there is no need to go back to old classification systems in which no clear description of disease entities was given; this will not serve any useful purpose for clinicians dealing with these conditions. In particular, since Campath-1H (Alemtuzumab) appears to be the treatment of choice in T-PLL,11,12 the correct diagnosis of this disease becomes clinically relevant. Although we recognize that there is a degree of morphological heterogeneity in T-PLL, the data on cytogenetics and molecular genetics are overwhelming, with 90% of patients having inversion 14(q11;q32) and abnormalities of chromosome 8 in 80%.7,9 Further advances will, of course, be welcome, but when one undertakes such studies, there is a need to investigate the patients adequately in every aspect – morphology, immunophenotype, cytogenetics and clinical manifestations – and then submit the material to further molecular analysis, for example, gene profiling. Such advances may or may not define new disease entities but will refine the diagnostic criteria and point to genes relevant to pathogenesis. In these and other conditions such as B-cell CLL, the way to progress is to agree on the basic data and then move forward with the new information.
E Matutes1 D Catovsky1
1 Academic Department of Haematology & Cytogenetics, The Royal Marsden Hospital, London, UK
References 1 Kussick SJ, Wood BL, Sabath DE. Mature T-cell leukemias which cannot be adequately classified under the new WHO classification of lymphoid neoplasms. Leukemia 2002; 16: 2457–2458. 2 Brouet JC, Sasportes M, Flandrin G, Preud’Homme JL, Seligmann M. Chronic lymphocytic leukaemia of T-cell origin. Immunological and clinical evaluation in eleven patients. Lancet 1975; 2: 890–893. 3 Matutes E, Brito-Babapulle V, Swansbury J, Ellis J, Morilla R, Dearden C et al. Clinical and laboratory features of 78 cases of T-prolymphocytic leukemia. Blood 1991; 78: 3269–3274. 4 Catovsky D, Matutes E. Leukemias of mature T cells. Neoplastic Hematopathol 2001; 43: 1589–1602. 5 Catovsky D, Ralfkiaer E, Muller-Hermelink HK. T-cell prolymphocytic leukaemia. In: Jaffe ES, Harris NL, Stein H, Vardiman JW, WHO Classification of Tumours of Haemopoietic and Lymphoid Tissues. Lyon: IARC Press, 2001; 195–196. 6 Matutes E, Garcia-Talavera J, O’Brien M, Catovsky D. The morphological spectrum of T-prolymphocytic leukaemia. Br J Haematol 1986; 64: 111–124. 7 Matutes E, Brito-Babapulle V, Dearden C, Yuille M, Catovsky D. Prolymphocytic leukemia of B and T cell types. Biology and therapy. Chronic Lymphoid Leukemias 2000; 24: 525–542. 8 Yuille MAR, Coignet LJA, Abraham SM, Yaqub F, Luo L, Matutes E et al. ATM is usually rearranged in T-cell prolymphocytic leukaemia. Oncogene 1998; 16: 789–796.
