Ph1-positive acute lymphocytic leukemia with chromosome 7 abnormalities.

A 56-yr-old woman with acute lymphocytic leukemia showed the presence of a Philadelphia chromosome in 90% of the bone marrow metaphases and in 10% of the peripheral blood metaphases. Part of the long arm of a G22 chromsome was translocated to the long arm of a C9 chromosome. A second cytogenetic abnormality was found in chromosome 7. Monosomy 7 was found in 60% of the marrow and in 20% of the peripheral blood metaphases. Chromosome 7q- was also found in a small percentage of the metaphases examined. Three months later, when the patient was in partial remission, only 10% of the marrow cells showed chromosome 7 monosomy and a Ph1 chromosome. During complete remission, no chromosomal abnormalities were found, except for a high breakage rate. The finding of a Ph1 chromosome in acute lymphocytic leukemia indicates that different precursors, both granulocytic and lymphocytic, may be involved in the Ph1 process.     

Azacitidine treatment for patients with myelodysplastic syndrome and acute myeloid leukemia with chromosome 3q abnormalities

Acute Myeloid Leukemia (AML) and myelodysplasia (MDS) with chromosome 3q abnormalities have a dismal outcome either untreated or with conventional treatments. Azacitidine (AZA) is now considered as the standard of care in high‐risk MDS and oligoblastic AML patients. The objective of this study was to evaluate the impact of azacitine treatment in this cytogenetic subgroup. We report here a multicentre retrospective study of 157 patients treated with AZA for AML/MDS with chromosome 3q abnormalities and 27 patients with isolated EVI‐1 overexpression. Median age was 65 years, 40 patients (25%) had inv(3)(q21q26.2) or t(3;3)(q21;q26.2), 36 patients (23%) had other balanced 3q26 rearrangements, 8 patients (5%) had balanced 3q21 rearrangements and 73 patients (46%) had other 3q abnormalities. The overall response rate was 50% (29% CR). Median overall survival was 10.6 months. By multivariate analysis, patients with lower bone marrow blast counts, higher platelet counts, non‐complex cytogenetics, and absence of prior treatment with intensive chemotherapy had a better outcome. 27 patients were allo‐transplanted and achieved a 21‐month median OS. Balanced 3q21 translocations were associated with a better response rate and overall survival. Outcome of patients with isolated EVI‐1 overexpression was comparable to that of patients with chromosome 3q lesions. Thus, AML/MDS patients with 3q abnormalities appear to be a heterogeneous group in their response to AZA, and AZA may represent a suitable option in particular as a bridge to allogeneic transplantation. Am. J. Hematol. 90:859–863, 2015. © 2015 Wiley Periodicals, Inc.     

14q32 translocations are associated with mixed-lineage expression in childhood acute leukemia

The frequency and characteristics of childhood acute leukemia with a 14q32 translocation [other than the t(8;14)(q24;q32)] were determined in 335 cases of newly diagnosed acute lymphoblastic leukemia (ALL) and 105 cases of acute nonlymphoblastic leukemia (ANLL). Ten children, representing 2.3% of the entire cohort, had this abnormality (1.5% of ALL patients and 4.8% of ANLL patients). By French-American-British (FAB) criteria, 4 cases were classified as L1, 1 as L2, 2 as M1, 1 as M2, and 2 as M5. Remarkably, mixed-lineage expression was found in 6 of these 10 cases, but in only 21 of the other 430 cases without a 14q32 translocation (P less than .001). Leukemic cells from 5 of these 6 cases (4 ANLL, and 1 ALL) coexpressed CD13, a myeloid-associated antigen, and CD2, a T-cell-associated antigen; blasts from the sixth case (ALL) coexpressed CD13 and CD19, a B-lineage-associated antigen. Thus, in addition to the well-described 11q23 translocations and t(9;22), 14q32 translocations also appear to be associated with mixed lineage antigen expression. Break-points of the reciprocal chromosomes from chromosome 14 were identified in five of these cases: 1q23, 6q23-q25, 7p15, 8q11, and 12q13. Of the four mixed-lineage cases that were tested, none showed rearrangement of the immunoglobulin heavy chain (IgH) gene. This suggests that the 14q32 breakpoint does not involve the IgH gene and that an unidentified important gene may reside on 14q32.     

Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11.

We report the results of two studies examining the genetic overlap between schizophrenia and velocardiofacial syndrome. In study A, we characterize two interstitial deletions identified on chromosome 22q11 in a sample of schizophrenic patients. The size of the deletions was estimated to be between 1.5 and 2 megabases. In study B, we examine whether variations in deletion size are associated with the schizophrenic phenotype in velocardiofacial syndrome patients. Our results show that a region of the genome that has been previously implicated by genetic linkage analysis can harbor genetic lesions that increase the susceptibility to schizophrenia. Our findings should facilitate identification and cloning of the schizophrenia susceptibility gene(s) in this region and identification of more homogeneous subgroups of patients.     

Rearrangements of chromosome 3 involving bands 3q21 and 3q26 are associated with normal or elevated platelet counts in acute nonlymphocytic leukemia

Fourteen patients with acute nonlymphocytic leukemia (ANLL) or dysmyelopoietic syndromes were found to have abnormalities involving the long arm of chromosome 3. In eight patients, the structural rearrangements involved both bands 3q21 and 3q26 and included t(3;3) (four patients), inv(3) (three patients), and ins(5;3) (one patient). Before treatment, seven of these eight patients had platelet counts above 100,000 per microliter, five had normal or elevated platelet counts, and four had significantly elevated platelet counts (600,000 to 1,731,000 per microliter). In each of the eight cases, normal or elevated platelet counts were associated with marked abnormalities of megakaryocytopoiesis, including increased numbers of megakaryocytes and numerous micromegakaryocytes. Classification within the French-American-British system was difficult in most of these cases; however, the leukemia in five of the eight patients with abnormalities of chromosome 3 that involved both bands 3q21 and 3q26 was classified as M4. The remaining six of the 14 patients had translocations between chromosome 3 and another chromosome. None involved both bands 3q21 and 3q26, and a break in either q21 or q26 was noted in only two patients. One of the six, who had ANLL (M4) with a normal platelet count, had a 3;5 translocation which involved band 3q25. These data suggest that in patients with ANLL, abnormalities of chromosome 3 which simultaneously involve bands 3q21 and 3q26 are associated with unusually high platelet counts.     

Poor prognosis in multiple myeloma is associated only with partial or complete deletions of chromosome 13 or abnormalities involving 11q and not with other karyotype abnormalities

Chromosomal abnormalities have major biologic and prognostic implications in leukemias. Cytogenetic information in typically hypoproliferative multiple myeloma (MM) is limited because of difficulties in obtaining analyzable metaphases. In this study, karyotypes and other known prognostic factors were analyzed in 155 newly diagnosed MM patients, entered on an intensive treatment program with two autotransplants. Complete remission (CR), event-free (EFS) and overall survival (OS) were analyzed using standard statistical methods. Abnormal cytogenetics were found in 39% of patients and were associated with a significantly lower CR rate (27% v 48%; P = .008). EFS and OS were inferior in patients with either partial or complete deletion of chromosome 13 or 11q abnormalities ("unfavorable" karyotype) when compared with the remaining patients (P < .001) who, as a group, had a similar prognosis irrespective of cytogenetic findings, ie, inevaluable, normal, or abnormal but without an "unfavorable" karyotype. The patients with abnormalities of both chromosomes 11 and 13 had a dismal prognosis with median EFS and OS of only 11 and 12 months, respectively. Significant associations were noted between an "unfavorable" karyotype and IgA isotype, elevated levels of beta-2 microglobulin (B2M, > or = 3 mg/L) and age > 60 years. On multivariate regression analysis, the absence of an "unfavorable" karyotype was the most significant variable associated with prolonged EFS and OS (P = .0001 and .0002, respectively). Other independent favorable variables were age less than 60 years, C-reactive protein (CRP) < or = 0.4 mg/dL and bone marrow plasmacytosis < or = 50% before treatment. On a multivariate analysis without cytogenetics, these same three standard parameters were identified as the only favorable variables. Patients not having all three standard favorable variables had a significantly lower CR rate (P = .03), EFS (P = .0001), and OS (P = .002) if an unfavorable karyotype was detected. We conclude that, in this program of uniformly treated MM patients, a poor prognosis was associated predominantly with abnormalities of chromosomes 11 and 13.     

Chromosome 3q21 abnormalities associated with hyperactive thrombopoiesis in acute blastic transformation of chronic myeloid leukemia

Two patients with acute blastic transformation of chronic myeloid leukemia (CML) associated with strikingly elevated platelet counts showed abnormalities of chromosome 3q in addition to the standard Philadelphia (Ph1) chromosome translocation. The first patient had an inversion of chromosome 3 (q21q26) cytologically identical to an inversion 3 previously reported in de novo acute megakaryoblastic leukemia, and the second patient showed a translocation between chromosome 3q and the chromosome 9 homologue not involved in the Ph1 translocation, [t(3;9)(q21;q34)]. Previous studies had incriminated either 3q21 or 3q26 as the locus for a regulatory thrombopoietic gene, but the current study suggests that 3q21 is the relevant site.     

Abnormalities of chromosome 1p/q are highly associated with chromosome 13/13q deletions and are an adverse prognostic factor for the outcome of high-dose chemotherapy in patients with multiple myeloma

The prognostic value of chromosomal abnormalities was studied in untreated multiple myeloma patients who were registered into a prospective randomised multicentre phase 3 study for intensified treatment (HOVON24). A total of 453 patients aged less than 66 years with stage II and III A/B disease were registered in the clinical study. Cytogenetic analysis was introduced as a standard diagnostic assay in 1998. It was performed at diagnosis in 160 patients and was successful in 137/160 patients (86%). An abnormal karyotype was observed in 53/137 (39%) of the patients. Abnormalities of chromosome 1p and 1q were found in 19 (36% of patients with an abnormal karyotype) and 21 patients (40%). There was a strong association between chromosome 1p and/or 1q abnormalities and deletion of chromosome 13 or 13q (n = 27, P < 0.001). Patients with karyotypic abnormalities had a significantly shorter overall survival (OS) than patients with normal karyotypes. Complex abnormalities, hypodiploidy, chromosome 1p abnormalities, chromosome 1q abnormalities, and chromosome 13 abnormalities were associated with inferior OS on univariate analysis, as well as after adjustment for other prognostic factors. In conclusion, chromosome 13 abnormalities and chromosome 1p and/or 1q abnormalities were highly associated, and are risk factors for poor outcome after intensive therapy in multiple myeloma.     

Molecular rearrangements on chromosome 11q23 predominate in infant acute lymphoblastic leukemia and are associated with specific biologic variables and poor outcome

Acute lymphoblastic leukemia (ALL) in infants generally shows distinctive biologic features and has a poor prognosis. Cytogenetic studies indicate that many infant leukemias have chromosome 11q23 translocations. Because of these findings and the distinct clinical features of infant leukemia, we investigated 30 cases of infant ALL for molecular defects of 11q23. Fourteen cases had cytogenetic abnormalities of 11q23, and all of them showed 11q23 rearrangements at the molecular level. An additional seven cases also had 11q23 molecular rearrangements, including one with normal cytogenetic analysis. Molecular abnormalities of 11q23 were significantly correlated with adverse prognostic factors, including age under 6 months, hyperleukocytosis, CD10- phenotype, and early treatment failure. Molecular analysis identified a group of infants with germline 11q23 that had a very good treatment outcome with a projected event-free survival of 80% at median follow-up of 46 months compared to 15% in infants with rearranged 11q23 (P < .001). These findings suggest that a high proportion (70%) of infants with ALL have 11q23 rearrangements and that these rearrangements are not always detectable by cytogenetic analysis. The presence of germline 11q23 DNA may identify a subgroup of infant ALL patients with a good outcome using current therapy and a different etiology for their ALL.     

Molecular analysis of chromosome 20q deletions associated with myeloproliferative disorders and myelodysplastic syndromes

Acquired deletions of the long arm of chromosome 20 are found in several hematologic conditions and particularly in the myeloproliferative disorders and myelodysplastic syndromes. The spectrum of diseases associated with 20q deletions suggests that such deletions may mark the site of a tumor suppressor gene that contributes to the regulation of normal multipotent hematopoietic progenitors. We present here the first detailed molecular analysis of 20q deletions associated with myeloid disorders. Thirty-four microsatellite primer pairs corresponding to loci on 20q have been used to study DNA samples from two cell lines and from highly purified peripheral blood granulocytes obtained from seven patients. In addition, Southern analysis of cell line DNA has been performed using 19 DNA probes that map to 20q. Three conclusions can be drawn from our results. Firstly, molecular heterogeneity of both centromeric and telomeric breakpoints was demonstrated, thus supporting the existence of a tumor suppressor gene on 20q. In addition many of the breakpoints have been mapped to small genetic intervals. Secondly, our results define a commonly deleted region of 16-21 cM which contains ADA, PLC1, TOP1, SEMG1, and PPGB. Several candidate tumor suppressor genes lie outside the common deleted region including SRC, HCK, p107, PTPN1, and CEBP beta. Thirdly, the data allow integration of genetic and physical maps and have refined the map positions of multiple genes. These results will facilitate attempts to identify candidate hematopoietic tumor suppressor genes on 20q.     

Morphologic characteristics of acute lymphoblastic leukemia (ALL) with abnormalities of chromosome 8, band q24.

The CALGB prospectively studied 140 adult acute lymphoblastic leukemia (ALL) patients for cytogenetic abnormalities. Seven (5%) patients with adequate cytogenetic preparations had t(8;14)(q24;q32) or t(8;22)(q24;q11). Patients were compared with non-8q24 patients for clinical and laboratory characteristics, response to therapy, and survival. The median age of patients with translocations involving 8q24 (71% males) was 40 years. Forty-three percent had lymphadenopathy, 29% splenomegaly, and 29% hepatomegaly. None exhibited central nervous system (CNS), skin, or gum involvement. These features did not differ significantly from non-8q24 ALLs. Patients with 8q24 translocations had higher hemoglobins (11.5 vs. 9.8 g/dl; P = 0.04) and lower percentage of blasts in the peripheral blood (8.5% vs. 69%; P = 0.007). Although all seven were finally categorized as ALL-L3, a marked variation in the proportion of typical L3 blasts was observed that initially resulted in the diagnoses of ALL-L2 in three cases and prolymphocytic leukemia in one. In five of five patients, the blasts typed as B cells (SIg+ and CD19+). Complete remission rates for patients with 8q24 translocations were 43%, whereas they were 68% for non-8q24 ALLS (P = 0.22). Furthermore, patients with 8q24 abnormalities exhibited significantly shorter survival (4.8 vs. 18.4 mo; P less than 0.001). We conclude that ALL with translocations of 8q24 in adults shows a mature B-cell immunophenotype (SIg+), poor prognosis and morphology ranging from classical ALL-L3 to ALL with a subpopulation of L3 cells. Thus, the diagnosis of ALL-L3 should be made when blastic cells possess a mature B-cell immunophenotype (SIg+) and an 8q24 translocation, even though the number of L3 cells is low.     

Ring/marker chromosome derived from chromosome 7 in childhood acute megakaryoblastic leukemia with monosomy 7

In some cases of childhood acute megakaryoblastic leukemia (AMKL), G-band analysis reveals supernumerary ring/marker chromosomes along with monosomy 7. However, their origin and relevance are poorly understood. We experienced three patients with AMKL, one of whom had Down’s syndrome, whose blasts at the first visit exhibited both monosomy 7 and a ring/marker chromosome. For one case, precise molecular-cytogenetic techniques revealed that the ring chromosome was derived from a chromosome 7. It was strongly suggested that the ring chromosome was derived from a chromosome 7 in another case. The ring or one of the 2 marker chromosomes was derived from a chromosome 7 in the other case. All patients responded well to initial induction therapy. While it is not clear whether the ring/marker chromosome 7 affects the long-term prognosis of acute myeloid leukemia with monosomy 7, it may be of prognostic relevance to distinguish pure monosomy 7 from monosomy 7 with a ring/marker chromosome 7. For this purpose, conventional G-banding could be complemented with additional techniques such as spectral karyotyping or fluorescence in situ hybridization, which characterize the aberration in more detail. These methods may be useful for determining the optimal treatment and for elucidating the etiology of AMKL itself.     

Translocations of 14q32 and deletions of 13q14 are common chromosomal abnormalities in systemic amyloidosis

Systemic monoclonal immunoglobulin light chain amyloidosis (AL) is associated with clonal plasma cell dyscrasias that are often subtle and non-proliferating. AL shares numerical chromosomal changes with multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS). Illegitimate translocations involving the immunoglobulin heavy chain gene (IGH) at 14q32 and deletions of the long arm of chromosome 13, [del(13q)], commonly occur in MM, MGUS and plasma cell leukaemia. In AL IGH rearrangements have been identified but, to date, there are no reports of del(13q). In this study of 32 patients with AL, 24 with systemic and eight with localized disease, translocations involving IGH and del(13q) were found using dual-colour interphase fluorescence in situ hybridization (FISH). IGH translocations were observed in 11 patients (37% overall and in 46% with systemic disease), of which nine had the IGH/CCND1 fusion from t(11;14)(q13;q32). Two showed IGH translocations other than the t(11;14) or t(4;14)(p16;q32). In one of these patients a breakpoint within the constant region of IGH between Calpha1 and Calpha2 was indicated. In the second a deletion covering Calpha1 and Calpha2 accompanied the translocation. Ten patients (27% overall and 33% of those with systemic disease) showed del(13q). The gain or loss of IGH and CCND1 signals provided evidence of numerical chromosomal changes in three patients.     

The spectrum of thyroid abnormalities in individuals with 18q deletions

Chromosome 18q deletions (18q-) are survivable autosomal deletions, having an estimated incidence of one in 40,000 live births. Our long-term goals were to 1) comprehensively define the endocrine phenotype, 2) determine the natural history, and 3) identify key genes leading to particular phenotypes. This report specifically emphasizes the thyroid phenotype. Medical record review and comprehensive clinical assessment(s) were performed on 120 individuals with 18q- at the Chromosome 18 Clinical Research Center, the largest group of individuals with 18q- ever assembled. Affected subjects ranged in age from 6 wk to 32 yr at initial assessment. Due to case reports of thyroid dysfunction in 18q deletions and the well-established association between hypothyroidism and aneusomies, we undertook thyroid testing in all individuals and completed TRH studies on 50 of them. Our studies demonstrated that 12% had hypothyroidism, and the results were consistent with primary thyroidal dysfunction. Furthermore, two individuals progressed from normal to abnormal over the course of 2 yr. Based on these studies, it appears that, as is the case in other aneusomies, annual thyroid testing, using TSH as a primary screening tool, is indicated. The mechanism of the hypothyroidism is not yet known, and the genetic basis has not been delineated.     

The spectrum of growth abnormalities in children with 18q deletions

The objective of this study was to assess the spectrum of growth abnormalities in children with 18q deletions. The growth axis of 50 individuals with a cytogenetically and molecularly confirmed 18q deletion was investigated by determining height, growth velocity, insulin-like growth factor I (IGF-I), IGF-binding protein-3, bone maturation, and response to pituitary stimulants of GH. Children with 18q deletions are short; 64% have a height more than -2 SD below the mean. Affected children also grow slowly; 68% have a growth velocity more than -1 SD below the mean. Half of the individuals have delayed bone maturation. Growth factors are skewed downward; 72% of the IGF-I values and 83% of the IGF-binding protein-3 values are below the mean for chronological age. Similarly, 72% of the children had a reduced or absent response to either of the GH stimulants, arginine and clonidine. In the total group of 50 children only 2 were normal for all parameters evaluated. Short stature and poor growth are common features of individuals with 18q deletions. GH deficiency is common in this cohort of patients and probably plays a role in the short stature seen in many of the affected individuals.