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Year : 2014  |  Volume : 57  |  Issue : 3  |  Page : 431-434
Loss of chromosome Y in acute lymphoblastic leukemia: Age related or neoplastic phenomenon?

1 Department of Cytogenetics, Tata Medical Center, Kolkata, India
2 Department of Laboratory Hematology, Tata Medical Center, Kolkata, India

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Date of Web Publication14-Aug-2014


Loss of chromosome Y (LOY) in the bone marrow has long been considered as an age-related phenomenon with an incidence of more than 25% in males beyond the age of 80 years. Though reported as an acquired abnormality in myeloid neoplasms, it has rarely been described in B-lymphoblastic leukemia which primarily is a disease of the young. We describe here in three cases of pediatric B-lymphoblastic leukemia with LOY. Conventional cytogenetic studies and fluorescence in situ hybridization studies using centromeric probes for chromosome X and Y on peripheral blood samples ruled out constitutional LOY in all the three cases favoring it to be a neoplastic phenomenon.

Keywords: Acquired abnormality, B-lymphoblastic leukemia, loss of chromosome Y, pediatric

How to cite this article:
Gupta A, Parihar M, Remani AS, Mishra DK. Loss of chromosome Y in acute lymphoblastic leukemia: Age related or neoplastic phenomenon?. Indian J Pathol Microbiol 2014;57:431-4

How to cite this URL:
Gupta A, Parihar M, Remani AS, Mishra DK. Loss of chromosome Y in acute lymphoblastic leukemia: Age related or neoplastic phenomenon?. Indian J Pathol Microbiol [serial online] 2014 [cited 2021 Sep 22];57:431-4. Available from: https://www.ijpmonline.org/text.asp?2014/57/3/431/138742

   Introduction Top

Loss of chromosome Y (LOY) in bone marrow samples can be present as a physiological phenomenon in elderly males, or as an acquired abnormality in hematological malignancies. It is a well-established cytogenetic abnormality in myeloid neoplasms and has been reported with varying frequency ranging from 5.1% to 16.4% in various hematological disorders. [1],[2],[3] There have been rare reports of a neoplasia associated LOY in pediatric B- lymphoblastic leukemia (B-ALL) however reports in adult B-ALL have suggested it to be an age-related phenomenon rather than a neoplastic one. [3],[4],[5] We describe herein three cases of pediatric B-ALL with a LOY suggesting its probable role in pathogenesis/progression of disease.

   Case report Top

Over a period of 20 months from September 2011 until June 2013, a total of 180 cases of ALL patients were seen in our institute and all underwent cytogenetic analysis as a standard protocol. Pediatric B-ALL accounted for 126 patients, of which 82 were males and 44 were females. Pediatric age group was defined as age 16 years and less. LOY was seen only in three cases of pediatric B-ALL. The clinical, hematopathological, and flowcytometric findings of these patients have been described in [Table 1]. The cytogenetic findings have been discussed in detail below.
Table 1: Clinical features of cases with loss of chromosome Y

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Cytogenetic material and methods

Conventional and fluorescence in situ hybridization (FISH) analysis was performed on peripheral blood (PB) and bone marrow aspirate (BMA) of all the three cases using standard protocols, which for BMA included two types of cultures one with and other without colcemid harvested after 17 h. PB cultures were harvested after 72 h of phytohemagglutinin (PHA) stimulation. GTG banded chromosomes were karyotyped and reported according to International System for Human Cytogenetic Nomenclature (ISCN) 2013. FISH was performed on BMA cultures as well as PB using XY centromeric probes (Abbott, Vysis) to confirm and rule out constitutional LOY.

Case 1

Conventional cytogenetic analysis of BMA showed two clones, one showing t(9;22)(q34;q11.2) with additional Philadelphia (Ph) chromosome, LOY and derivative chromosome 15 in 16 metaphases and the other showing t(9;22) with t(1;19) in four metaphases. The karyotype as per ISCN 2013 was reported as 46,X,-Y,t(9;22)(q34;q11.2),der(15)t(?11;15)(q12;p11.2),+der(22)t(9;22)[16]/46,XY, t(9;22)(q34;q11.2),der(19)t(1;19)(q23;p13)[4] [Figure 1]a. PHA stimulated PB cultures showed a normal karyotype along with FISH using probe for XY showed normal XY pattern in 100% of cells ruling out constitutional LOY as well as low level constitutional mosaicism [Figure 2]a and b. The patient was started on BFM 95 ALL protocol along with Imatinib and remains in morphological remission up till the last follow-up of 11 months postdiagnosis with 5% Ph+ cells on FISH suggesting persistence of disease while a repeat FISH on BMA sample using probe for XY showed no LOY. The flow cytometric immunophenotyping of this case showed that the cells in the blast region expressed Tdt, CD34, CD10, cCD22, CD19, CD2, cCD3, and HLA-DR and were negative for CD7, CD4, CD8, CD117, CD5, CD14, CD13, CD33, cCD79a, and cMPO. It was reported as mixed phenotype acute leukemia (B/T).
Figure 1: (a-c) GTG banded karyotypes showing loss of Y chromosome (LOY). (a) Case 1 showing LOY along with t(9;22) with gain of an extra Philadelphia chromosome and an unbalanced translocation between
the short arm of chromosome 15 and long arm of chromosome 11 (arrows) (×1000 oil immersion). (b) Case 2 showing a hyperdiploid clone (modal number 54-55) with gains of multiple chromosomes and
LOY in a male patient (×1000 oil immersion). (c) Case 3 showing LOY along with an insertion of a segment of the long arm of chromosome 11 into the short arm of chromosome 1 (abnormalities marked by
arrows) (×1000 oil immersion)

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Figure 2: (a and b) Fluorescent in situ hybridization (FISH) using XY probe on bone marrow and peripheral blood (PB). (a) Metaphase and interphase FISH on bone marrow aspirate cultures from case 1 using CEP X Spectrum orange/Y Spectrum green probe (Vysis, Abbott ) shows loss of chromosome Y (LOY) in the metaphase and normal pattern in the interphase cells (×1000 oil immersion). (b) Interphase FISH on PB from case 1 using CEP X Spectrum orange/Y Spectrum green probe (Vysis, Abbott ) shows normal signal pattern suggesting no LOY (×1000 oil immersion)

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Case 2

Karyotyping showed the presence of a hyperdiploid clone in nine metaphases with a modal number of 54-55 with LOY in all the nine metaphases. The final karyotype was reported as 54-55,XX,-Y,+4,+5,+6,+8,+9,+10,+12,+14,+17,+18,+21[CP9] /46,XY[11] (ISCN 2013) [Figure 1]b. The LOY was also confirmed by FISH on BMA. A constitutional loss was ruled out as in the first case. The patient was started on UKALL protocol and is presently in remission 6 months after diagnosis.

Case 3

Cytogenetic analysis showed a neoplastic clone characterized by an insertion of a segment of the long arm of chromosome 11 (q21q23) into the short arm of chromosome 1 in 18 metaphases. This was associated with LOY in 15 metaphases. FISH done on BMA cultures using MLL break a part probe (Abbott Vysis) showed no involvement of the MLL gene. The karyotype was reported as 46,XY,ins(1;11)(p36.1;q21q23)[3]/45,idem,-Y[15]/46,XY[2] (ISCN 2013) [Figure 1]c. Similar to the previous cases cytogenetic and FISH analysis of PB did not reveal any constitutional LOY.

   Discussion Top

Physiological LOY is rarely reported below the age of 50 years, though its incidence rises to 25% or more in males beyond 80 years. [6] In tumor biology loss of specific genetic material is known to be associated with loss of specific tumor suppressor genes. Although it is not known whether the chromosome Y harbors tumor suppressor genes, LOY has been observed in numerous solid tumors and epithelial malignancies. [7],[8],[9] In hematological malignancies LOY in the bone marrow samples has been debated to be an age-related phenomenon rather than a neoplastic one. Wong et al. in their study on myeloid neoplasms have stated that myeloid neoplasms such as acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and myelodysplastic syndromes (MDS), are associated with an elderly population hence questioning the association of LOY as an acquired abnormality. [3] Some authors have suggested that LOY is more of an age-related phenomenon as it is not seen in B-ALL which primarily is a disease of the young. [4] LOY is a well-established acquired abnormality in myeloid neoplasms and the most common secondary abnormality in t(8;21) AML, which commonly occurs in young adults. [10]

Huh et al. in 2007 studied bone marrow samples from 868 patients with hematological diseases and found loss of sex chromosomes in 5.1% of patients. [1] However, none of these patients had B-ALL. Of the 82 pediatric male patients seen in our institute over a period of 20 months, 3.6% had LOY. In our first patient, the LOY was seen as a secondary abnormality or a sub-clone in the progression of a Ph+ tumor. Secondary abnormalities are known to occur in Ph+ B-ALL and are associated with a worse prognosis; however, LOY has never been reported as a secondary abnormality in Ph+ B-ALL. Heerema et al. analyzed the additional chromosomal aberrations in 326 Ph+ pediatric B-ALLs and found that patients with losses of chromosomes as additional abnormality had worst prognosis, although no patient was reported with a LOY as seen in our patient. [11] The other interesting findings in this case were the biphenotypic nature of the leukemic clone, the presence of additional Ph chromosome and t(1;19) as secondary abnormalities.

In case 2, the LOY was seen in all the neoplastic clonal metaphases suggesting that this abnormality probably existed right from the time of leukemogenesis, while in the third case the LOY occurred in the sub-clone similar to case 1 suggesting a possible role of LOY in progression of the disease. Clonal architecture and sub-clone development in B-ALLs is a dynamic process. The sub-clones have kaleidoscopic genetics with nonlinear complex evolution and do not follow any preferential order of appearance. [12] The importance of this clonal phenomenon is known to have an important bearing on treatment and relapse of the neoplastic process. [13],[14] However, no such attempt was made in this study due to small number of cases along with presence of confounding factors like Ph chromosome and other structural abnormalities some of which had no known clinical significance.

Though the Y chromosome is known to predominantly harbor the sex linked genes, the pseudo-autosomal regions (PAR) of the Y chromosome carry genes that are inherited just like other autosomal genes. [15] Males carry two alleles of these genes. It will be interesting to see whether losses of these genes have a haploinsufficiency effect, or mutations in the genes present in PAR of the X chromosome can be oncogenic in the absence of its homolog on the Y chromosome.

Vijayakumar et al. have shown that the chromosome Y suppresses prostate cancer in a human prostate cancer cell line suggesting that the Y chromosome may be harboring some tumor suppressor genes. [16] Recently mutations and rearrangements in cytokine receptor-like factor 2 gene located at the PAR1 at Xp22.3/Yp11.3 have been found in up to 7% of B-ALLs. [17]

The roles of other genes present in the PAR need further classification and investigation. The micro HLA antigens encoded by genes present on Y chromosome are known to play a role in graft versus leukemia (GVL) effect in female to male hematopoietic stem cell transplantation. [18] The LOY in these patients can alter the GVL effect increasing the probability of relapse in these patients. [19] To conclude our article suggests that LOY can also be seen as a neoplastic abnormality acquired in B-ALL, rather than just an age-related phenomena.

   References Top

Huh J, Moon H, Chung WS. Incidence and clinical significance of sex chromosome losses in bone marrow of patients with hematologic diseases. Korean J Lab Med 2007;27:56-61.  Back to cited text no. 1
Zhang LJ, Shin ES, Yu ZX, Li SB. Molecular genetic evidence of Y chromosome loss in male patients with hematological disorders. Chin Med J (Engl) 2007;120:2002-5.  Back to cited text no. 2
Wong AK, Fang B, Zhang L, Guo X, Lee S, Schreck R. Loss of the Y chromosome: An age-related or clonal phenomenon in acute myelogenous leukemia/myelodysplastic syndrome? Arch Pathol Lab Med 2008;132:1329-32.  Back to cited text no. 3
Abeliovich D, Yehuda O, Ben-Neriah S, Or R. Loss of Y chromosome. An age-related event or a cytogenetic marker of a malignant clone? Cancer Genet Cytogenet 1994;76:70-1.  Back to cited text no. 4
Padre-Mendoza T, Farnes P, Barker BE, Smith PS, Forman EN. Y chromosome loss in childhood leukaemias. Br J Haematol 1979; 41:43-8.  Back to cited text no. 5
Herens C, Brasseur E, Jamar M, Vierset L, Schoenen I, Koulischer L. Loss of the Y chromosome in bone marrow cells: Results on 1907 consecutive cases of leukaemia and preleukaemia. Clin Lab Haematol 1999;21:17-20.  Back to cited text no. 6
Berrieman HK, Ashman JN, Cowen ME, Greenman J, Lind MJ, Cawkwell L. Chromosomal analysis of non-small-cell lung cancer by multicolour fluorescent in situ hybridisation. Br J Cancer 2004;90:900-5.  Back to cited text no. 7
König JJ, Teubel W, Romijn JC, Schröder FH, Hagemeijer A. Gain and loss of chromosomes 1, 7, 8, 10, 18, and Y in 46 prostate cancers. Hum Pathol 1996;27:720-7.  Back to cited text no. 8
Minner S, Kilgué A, Stahl P, Weikert S, Rink M, Dahlem R, et al. Y chromosome loss is a frequent early event in urothelial bladder cancer. Pathology 2010;42:356-9.  Back to cited text no. 9
Parihar M, Kumar JA, Sitaram U, Balasubramanian P, Abraham A, Viswabandya A, et al. Cytogenetic analysis of acute myeloid leukemia with t(8;21) from a tertiary care center in India with correlation between clinicopathologic characteristics and molecular analysis. Leuk Lymphoma 2012;53:103-9.  Back to cited text no. 10
Heerema NA, Harbott J, Galimberti S, Camitta BM, Gaynon PS, Janka-Schaub G, et al. Secondary cytogenetic aberrations in childhood Philadelphia chromosome positive acute lymphoblastic leukemia are nonrandom and may be associated with outcome. Leukemia 2004;18:693-702.  Back to cited text no. 11
Anderson K, Lutz C, van Delft FW, Bateman CM, Guo Y, Colman SM, et al. Genetic variegation of clonal architecture and propagating cells in leukaemia. Nature 2011;469:356-61.  Back to cited text no. 12
Konrad M, Metzler M, Panzer S, Ostreicher I, Peham M, Repp R, et al. Late relapses evolve from slow-responding subclones in t(12;21)-positive acute lymphoblastic leukemia: Evidence for the persistence of a preleukemic clone. Blood 2003;101:3635-40.  Back to cited text no. 13
Schnittger S, Bacher U, Dicker F, Kern W, Alpermann T, Haferlach T, et al. Associations between imatinib resistance conferring mutations and Philadelphia positive clonal cytogenetic evolution in CML. Genes Chromosomes Cancer 2010;49:910-8.  Back to cited text no. 14
Grskoviæ B, Mrsiæ G. Y chromosome: From evolution to forensics - An overview. Acta Med Croatica 2010;64:33-40.  Back to cited text no. 15
Vijayakumar S, Garcia D, Hensel CH, Banerjee M, Bracht T, Xiang R, et al. The human Y chromosome suppresses the tumorigenicity of PC-3, a human prostate cancer cell line, in athymic nude mice. Genes Chromosomes Cancer 2005;44:365-72.  Back to cited text no. 16
Russell LJ, Capasso M, Vater I, Akasaka T, Bernard OA, Calasanz MJ, et al. Deregulated expression of cytokine receptor gene, CRLF2, is involved in lymphoid transformation in B-cell precursor acute lymphoblastic leukemia. Blood 2009;114:2688-98.  Back to cited text no. 17
Randolph SS, Gooley TA, Warren EH, Appelbaum FR, Riddell SR. Female donors contribute to a selective graft-versus-leukemia effect in male recipients of HLA-matched, related hematopoietic stem cell transplants. Blood 2004;103:347-52.  Back to cited text no. 18
Wolff D, Knopp A, Weirich V, Steiner B, Junghanss C, Casper J, et al. Loss of the GVL effect by loss of the Y-chromosome as putative mechanism of immune escape in ALL. Bone Marrow Transplant 2005;35:101-2.  Back to cited text no. 19

Correspondence Address:
Mayur Parihar
Department of Cytogenetics, Tata Medical Center, Kolkata - 700 156
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0377-4929.138742

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  [Figure 1], [Figure 2]

  [Table 1]

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