Monosomy 16 as the Sole Abnormality in Myeloid Malignancies

Monosomy 16 as the Sole Abnormality in Myeloid Malignancies Eva M. McGhee, Norman R. Cohen, Jeffrey L. Wolf, Carmelita T. Ledesma, and Philip D. Cotter

ABSTRACT: The majority of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients reported with chromosome 16 abnormalities had the inv(16)(p13q22) or t(16;16)(p13;q22) rearrangements, which were associated with a favorable prognosis. In contrast, del(16)(q22) was reported less commonly but was associated with a less favorable prognosis. We describe an 80-year-old woman who presented with MDS (refractory anemia). Chromosome analysis from bone marrow aspirate cultures showed monosomy 16 as the sole cytogenetic abnormality. Comparison of this patient with previously reported cases of monosomy 16 showed that this uncommon abnormality was associated with myeloid disorders. Monosomy 16 patients, similar to del(16)(q22) patients, tended to be elderly, presented with MDS or AML, and had a poor prognosis. The similarity in clinical course for del(16)(q22) and monosomy 16 patients suggests that the phenotype in both groups resulted from loss of important gene(s) on 16q, as distinct from the fusion gene product identified in the inv(16) and t(16;16) rearrangements. © Elsevier Science Inc., 2000. All rights reserved. INTRODUCTION Chromosome 16 abnormalities are common in acute myeloid leukemia (AML) and the myelodysplastic syndromes (MDSs). The most frequent and well characterized are inv(16)(p13q22) and t(16;16)(p13;q22), which account for 8% of AML [1]. The majority of patients with inv(16) or t(16;16) are classified as acute myelomonocytic leukemia (AML-M4) with bone marrow eosinophilia (AML-M4Eo) [2–4]. Deletions of the long arm of chromosome 16 [del(16) (q22)] are less frequently reported than are the inv(16) (p13q22) and t(16;16)(p13;q22) rearrangements and are generally not associated with AML-M4Eo. Patients with del(16)(q22) usually present with MDS, such as refractory anemia with excess of blasts (RAEB) or chronic myelomonocytic leukemia, which typically transforms into acute myeloblastic leukemia with maturation (AML-M2) or AML-M4 [5–7]. Complete monosomy for chromosome 16 is uncommon and has been reported as the sole abnor-

From the Department of Pediatrics, Division of Medical Genetics, University of California at San Francisco (E.M.M., P.D.C.), San Francisco, California, USA; Alta Bates Comprehensive Cancer Center (N.R.C., J.L.W.), Berkeley, California, USA; and the Division of Medical Genetics, Children’s Hospital Oakland (C.T.L., P.D.C.), Oakland, California, USA. Address reprint requests to: Philip D. Cotter, Ph.D., Division of Medical Genetics, Children’s Hospital Oakland, 747 Fifty Second Street, Oakland, CA 94609. Received July 2, 1999; accepted September 1, 1999. Cancer Genet Cytogenet 118:163–166 (2000)  Elsevier Science Inc., 2000. All rights reserved. 655 Avenue of the Americas, New York, NY 10010

mality in only six previous cases (Table 1). In this communication, we report an additional patient with monosomy 16 as the sole cytogenetic abnormality and compare the clinical course of monosomy 16 patients with those patients having del(16q)(q22) and inv(16)(p13q22) or t(16;16)(p13;q22). CASE REPORT An 80-year-old Caucasian woman (S. M.) initially presented to her cardiologist (in September 1998) with shortness of breath and evidence of heart failure. At that time, she was noted to have a hemoglobin (Hb) of 7 g/dL (normal: 13–16.3 g/dL). She was subsequently treated for congestive heart failure and referred for further evaluation. Physical examination revealed evidence of skin and mucus membrane pallor. There was no peripheral lymphadenopathy, hepato- or splenomegaly, bone pain, or tenderness. Her past medical history was largely unremarkable. She had no history of toxic exposures to chemicals or radiation, and she had been taking medications primarily related to her cardiac disease, including Zestril, Digoxin, Indapamine, and nitroglycerin. She had also been on hormone replacement therapy and Coumadin. She previously had a myocardial infarction, a cerebral vascular accident, and uterine cancer for which a hysterectomy was performed. Family history revealed that her mother died of leukemia at age 67 and one sibling died of colon cancer. Her four children were in good health.

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Table 1 Reports of hematologic malignancies with monosomy 16 as the sole cytogenetic abnormality Reference

Age

Classification

Karyotype

Survival

Kardon et al., 1982 [8] Yunis et al., 1984 [9] Lindquist et al., 1985 [10] Swolin et al., 1988 [11]

73 26 22 68

RAEB AML-M4 AML-M2 PV

45,XY,⫺16/46,XY 45,XY,⫺16[3]/46,XY[36] 45,XY,⫺16[3]46,XY[10] 45,XY,⫺16/46,XY

34 m 6m NR 165 m

Palka et al., 1990 [12] Palka et al., 1990 [12] Present case

65 79 80

RAEB RAEB RA

45,XX,⫺16[4]/46,XX[16] 45,XY,⫺16[4]/46,XX[20] 45,XX,⫺16[6]/46,XX[14]

29 m 1m ⬎9 m

Other Transformed into acute leukemia 82% blasts; WBC:60.0 ⫻ 109/L 18% abnormal cells; subsequently developed “myeloid metaplasia” with a 46,XY,del(12p)/46,XY karyotype

Diagnosed 9/98; RAEB at 9 m

Abbreviations: AML, acute myeloid leukemia; m, month(s); NR, not reported; PV, polycythemia vera; RA, refractory anemia; RAEB, refractory anemia with excess of blasts; WBC, white blood cells.

Laboratory data revealed an Hb of 6.7 g/dL, white blood cell count of 3.2 ⫻ 109/L (normal: 4.8–10.8 ⫻ 109/L), and platelet count of 83 ⫻ 109/L (normal: 150–350 ⫻ 109/L). The differential count showed 34% netrophils, 47% lymphocytes, and 10.9% monocytes. Erythrocytes were macrocytic with a mean corpuscular volume of 126 fl (normal: 80–99 fl) and a mean corpuscular hemoglobin of 34.7 pg (normal 27–34 pg). Reticulocyte count was 0.9% corrected. Peripheral smears showed minimal polychromasia and failed to reveal any evidence of abnormal cells. Subsequent studies showed a slightly elevated lactate dehydrogenase of 248 U/L (normal range: 110–220 U/L), elevated serum ferritin of 465 ␮g/L (normal: 15–300 ␮g/L), elevated serum folate level ⬎20 ␮g/L (normal: 2–9 ␮g/L), and a normal B12 level of 614 ng/L. Serum protein electrophoresis/ immunoelectrophoresis demonstrated no evidence of monoclonal gammapathy. Quantitative immunoglobulin G (IgG), IgA, and IgM were within normal limits. A bone marrow biopsy showed a cellularity of 25–30% with mild relative erythroid hyperplasia, a relative reduction of the myeloid series, and small numbers of megakaryocytes. No abnormal infiltrates were noted. Repeat bone marrows at 3 and 4 months showed a cellularity of 25–30% with relative erythroid hyperplasia. The myeloid series showed a slight leftward shift without clusters or sheets of blasts. The marrow smears were scant and were difficult to interpret. The overall impression was that the marrow was not diagnostic but most likely indicated a myelodysplastic syndrome (refractory anemia). The patient has been treated symptomatically with red cell mass and observation. A bone marrow, at 9 months after presentation, showed progression with greater than 10% blasts and was classified as refractory anemia with excess of blasts. Cytogenetic analysis was performed on GTG-banded metaphases from direct and 48-hour bone marrow cultures 3 months after presentation. Monosomy of chromosome 16 was the sole abnormality identified: 45,XX,⫺16 [6]/46,XX[14]. DISCUSSION Chromosome 16 abnormalities, in particular inv(16) (p13q22) and t(16;16)(p13;q22), are common in AML and

MDS [1]. Both the inv(16) and t(16;16) rearrangements result in a fusion transcript from the juxtaposition of the smooth muscle myosin heavy chain gene (MYH11) at 16p13 and the core-binding transcription factor ␤-subunit gene (CBF␤) at 16q22 [13, 14]. The CBF␤ gene product normally forms a heterodimer with the core-binding transcription factor ␣-subunits (CBF␣1–3). However, the MYH11/CBF␤ fusion protein was recently shown to sequester the CBF␣ complex in the cytoskeleton, resulting in reduction of CBP␣-regulated gene transcription [15]. Patients with inv(16) and t(16;16) predominantly present with an AML-M4Eo phenotype, and the presence of these rearrangements is associated with a good prognosis and a high rate of remission [3, 16]. Early studies reported that patients with deletions of the long arm of chromosome 16 [del(16)(q22)] had a phenotype and prognosis similar to those with the inv(16) [17, 18]. Indeed, some early del(16)(q22) patients were described with AML-M4Eo [19] and cryptic fusion products were subsequently identified in some del(16)(q22) patients with AML-M4Eo [20]. Similarly, identification of CBF␤/MYH11 fusion transcripts by the reverse transcriptase–polymerase chain reaction resulted in the reclassification of several del(16)(q22) chromosomes to inv(16) [21]. However, more recent evaluations of larger numbers of patients showed that there was a difference in phenotypes between inv(16) and del(16) patients and that del(16) patients had a less favorable prognosis [5–7]. In general, patients with del(16)(q22) were more likely to be elderly, to respond poorly to treatment, and to initially present with MDS, transforming into AML (most commonly M4) and progressing to complex karyotypes [5–7]. The molecular pathogenesis of the del(16)(q22) is unknown but is likely to include the loss of key gene(s), as distinct from the fusion product seen with the inv(16) and t(16;16) rearrangements. The patient described here presented with refractory anemia, and monosomy 16 was identified as the sole cytogenetic abnormality in bone marrow cultures. By 9 months after presentation, the bone marrow showed refractory anemia with excess blasts. Only six other patients were previously reported with monosomy 16 as the sole abnormality (see Table 1). In general, the monosomy 16 patients were similar to the del(16)(q22) patients [5–7].

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Monosomy 16 in Leukemia Monosomy 16 patients were predominantly elderly, presented with MDS or AML, and had a poor prognosis (from 1- to 34-month survival time; see Table 1). The exception was the patient reported by Swolin et al. [11], who originally presented with polycythemia vera and survived 165 months after diagnosis. As with del(16)(q22), monosomy 16 was primarily associated with myeloid disorders (see Table 1). Although all but one of the monosomy 16 patients had MDS or AML, none were described with AML-M4Eo. Two other patients with myeloid disorders were reported with monosomy 16 as a clonal abnormality. The patient described by Keuh et al. [22] was a 58-year-old woman with RAEB and a 45,XX,⫺5/45,XX,⫺16/46,XX karyotype. Piva et al. [23] described a 19-year-old girl with AML-M5 and a 45,XX,⫺7[8]/45,XX,⫺16[2]/44,XX,⫺7, ⫺16[2]/46,XX[1] karyotype. Data on the survival of both patients was not reported [22, 23]. Monosomy 16 was also common as a secondary feature or as part of a complex karyotype in MDS and AML [24]. Interestingly, Li et al. [25] reported three patients with a dic(16;22)(q11;p11) chromosome. In effect, these patients had monosomy for 16q. All three patients had myeloid abnormalities: two with AML-M4 and one with therapy related MDS. However, only one of these patients presented with the dic(16;22) as the sole cytogenetic abnormality; a 74-yearold woman whose disease transformed into AML-M4 after a 1-year history of MDS, with a subsequent 5-month survival [25]. Patients with del(16)(q22), monosomy 16, and dic(16;22) all presented with myeloid disorders, and the common cytogenetic feature was monosomy/loss of heterozygosity (LOH) for the region 16q22→qter. Studies have implicated regions on 16q in which LOH was associated with various neoplasias [26]. LOH for the cell adhesion molecule E-caderin gene (CDH1) at 16q22.1 has been implicated in the development of primarily epithelial neoplasias [27]. Recently, Filippova et al. [26] identified a novel tumor-suppressor gene, CTCF, from the 16q22.1 region. The CTCF gene encodes a DNA-binding nuclear protein that was shown to be a transcriptional repressor of the MYC oncogene [26] and was expressed in myeloid cells [28]. Overexpression of MYC is a common theme in carcinogenesis, so it is tempting to speculate that LOH for the CTCF locus at 16q22.1 may result in upregulation of MYC in the del(16)(q22) and monosomy 16 patients. However, investigation of LOH for CTCF in del(16)(q22) or MYC activity in monosomy 16 or del(16)(q22) patients has not been reported to date. In summary, patients with monosomy 16 as the sole cytogenetic abnormality are uncommon but present with a phenotype similar to that of del(16)(q22) patients and distinct from the phenotype and clinical course associated with the inv(16) or t(16;16) rearrangements. Although only seven patients with monosomy 16 as the sole cytogenetic abnormality have been reported to date, they had a generally poor prognosis, similar to the del(16)(q22) patients. Because patients with monosomy 16, dic(16;22), and del(16)(q22) had a similar phenotype and clinical course, it is likely that the pathogenesis of these rearrangements is the same and likely a result of loss of heterozygosity for an important gene(s) in the region 16q22→qter.

The reporting of a larger number of patients with monosomy 16 is important to more accurately determine the clinical course and prognosis.

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