ALBERT

Description: We studied the clinical, morphological, and immunologic characteristics of 11 patients with 11q translocation-associated acute leukemia. There were three patients with t(9;11)(p22;q23), one with a variant of the t(9;11), three with t(11;19)(q23;p13), two with t(1;11)(p32;q23), one with t(10;11)(p15;q22or23), and one with t(11;17) (q23;q25). The breakpoints in chromosome 11 clustered in band q23. The morphological feature was FAB-M5 in two patients, FAB-M2 in one, FAB-L1 in six, and lymphoblastic lymphoma in one. The remaining patient underwent morphological changes from FAB-L1 seen at the time of diagnosis to M5b at relapse. Immunologic marker studies in ten patients revealed that one had T cell type; another pre-B cell type; three CALLA- Ia- non-T, non-B type; two CAL-LA- Ia+ non-T, non-B type; two monocytic type (positive Fc-receptor); and the remaining one underwent phenotypic changes from CALLA+ Ia+ non-T, non-B type to monocytic type. The patients were usually young; five were under 1 year and two were 9 and 13 years. Hyperleukocytosis was observed in eight of the ten patients with acute leukemia, and two of the eight died of intracranial hemorrhage within two days of admission, associated with disseminated intravascular coagulation. These findings indicate that leukemia with the 11q23 translocation share certain characteristics in common, irrespective of the recipient chromosome, even though the latter may have some influence on the morphological and immunologic phenotype. Our data provide a hypothesis that multipotent stem cells are involved in the genesis of the 11q translocation-associated leukemia.

Description: A child who had acute lymphoblastic leukemia (ALL) associated with an 8;14 chromosome translocation and with a pre-B phenotype is described. The leukemic cells were determined to be pre-B-cells on the basis of intracytoplasmic mu-chain immunoglobulin (cIgM+) and the common-ALL antigen, lack of receptors for sheep erythrocytes, and lack of surface immunoglobulin. The 8;14 translocation is frequently found in patients with Burkitt's lymphoma and in most patients with B-cell ALL and is known to carry a poor prognosis. Thus far, no karyotypes have been reported for patients with pre-B-ALL. The present case indicates that a 14q+ chromosome may provide a proliferative advantage not only to cells with a B-cell phenotype, but also to pre-B-cells. The short survival of our patient also suggests that the 14q+ abnormality and the pre-B phenotype may signal a poor prognosis.

Description: Cytogenetic and pathologic studies were performed on six patients with angioimmunoblastic lymphadenopathy (AILD). All six had diffuse lymphadenopathy; five had fever, four had weight loss, and four had a diffuse erythematous rash. All patients except one had a polyclonal elevation of immunoglobulin. All patients had diagnostic findings in lymph node (LN) and bone marrow (BM) biopsies. Two patients died of progressive AILD; one patient died after transformation of AILC to immunoblastic sarcoma (IBS); one patient died of gastrointestinal bleeding of unknown cause. The remaining two patients, who have achieved complete remission with intensive chemotherapy, are alive 20 and 8 mo after the diagnosis; one of these had AILD and the other, both AILD and IBS. Despite diagnostic BM biopsy findings, none of the patients had chromosome abnormalities in their BM cells. In studying LN cels of 5 patients, however, we found chromosome abnormalities in each; clonal abnormalities were detected in two, both clonal and nonclonal abnormalities in two, and only nonclonal single-cell abnormalities in one. An extra chromosome 3, seen in four patients, was clonal in two and nonclonal in the two others. Cells with +5, +15, +19, +21, +22 were seen in two patients. All patients had 50% or more normal dividing cells in their LN. The mosaicism of unrelated abnormal cells in their LN. The mosaicism of unrelated abnormal karyotypes that was seen in four patients suggests that this malignant tumor is not necessarily monoclonal in its early stages, but that one clone may be selected and predominate in the late stage. Because nonrandom acquired clonal chromosome abnormalities are a consistent feature of malignancies, our data suggest that AILD may be a malignant disease despite its original description as a benign proliferative process. Therefore, it may require aggressive chemotherapy.

Description: Chromosome and cytologic studies were performed on three Down's syndrome (DS) patients with acute nonlymphocytic leukemia (ANLL). All three patients had an aneuploid clone in their leukemic cells: 50, XX, +6, +19, +21, +22, +8, XX, +21, and 47,XY, +8, - 21 +dic(21;21)(p13;p11). Every patient appeared to have acute undifferentiated leukemia when the blast cells were examined with Wright-Giemsa stain; cytochemistry studies, however, showed that the leukemic blasts were in an early stage of myeloid differentiation. The two patients with +8 had a preleukemic phase; the blast cells of the patient with an extra no. 19 and no.22 could not be differentiated morphologically from those of the two patients with an extra no. 8. Our findings and a review of data on 40 other patients suggest that most DS children with ANLL have hyperdiploidy, which is usually related to gains of C, F, and /or G chromosomes, and that the abnormalities of +8 and of +19, +22 in DS children may be associated with acute leukemia (AL) in an early stage of myeloid differentiation.

Description: We studied the karyotype in 26 children with ANLL, which was diagnosed on the basis of the FAB classification. Clonal chromosome abnormalities were found in 21 of 26 patients. Four patients, including 3 with Down's syndrome, had AML(M1). Nine patients, including 3 with t(8;21), had AML(M2). All 3 patients with APL(M3) had t(15;17). Four patients had AMMOL(M4); 3 of these had a normal karyotype. Six patients had AMOL(M5); 5 and 11q rearrangements, and 3 of these had a break in 11q23. Only one patient had EL(M6), and he had a normal karyotype. One patient with t(11;19), classified as AML(M2) on Wright-Giemsa-stained cells, had a strong alpha-naphthyl acetate esterase reaction, indicating that the leukemic cells had a cytochemical feature characteristic of monocytes. Whereas t(8;21) and t(15;17) are uniquely associated with AML(M2) and APL(M3), respectively, the 11q rearrangements are also seen in AML(M1/M2), although they are more common in AMOL(M5) and AMMOL(M4). The case with t(11;19) suggests that cells with 11q rearrangements and with AML(M1/M2) may have both monocytic and granulocytic features. When we used our data and previous reports on 243 aneuploid patients (169 adults and 74 children) to correlate the chromosome abnormalities with patient age, we found differences in the chromosome pattern seen among various age groups. This suggests that different etiologic factors as well as changes in host susceptibility may influence the development of and the karyotypic pattern in the various types of leukemia. Moreover, the frequency of various chromosome abnormalities in childhood ANLL can provide a baseline for comparison of the frequency of the same abnormality in adults. The karyotypic analysis of childhood ANLL is important not only because of the information that can be obtained about childhood ANLL, but also because the data can provide substantial insight into the etiology of ANLL in adults.

Description: Cytogenetic and pathologic studies were performed on six patients with angioimmunoblastic lymphadenopathy (AILD). All six had diffuse lymphadenopathy; five had fever, four had weight loss, and four had a diffuse erythematous rash. All patients except one had a polyclonal elevation of immunoglobulin. All patients had diagnostic findings in lymph node (LN) and bone marrow (BM) biopsies. Two patients died of progressive AILD; one patient died after transformation of AILC to immunoblastic sarcoma (IBS); one patient died of gastrointestinal bleeding of unknown cause. The remaining two patients, who have achieved complete remission with intensive chemotherapy, are alive 20 and 8 mo after the diagnosis; one of these had AILD and the other, both AILD and IBS. Despite diagnostic BM biopsy findings, none of the patients had chromosome abnormalities in their BM cells. In studying LN cels of 5 patients, however, we found chromosome abnormalities in each; clonal abnormalities were detected in two, both clonal and nonclonal abnormalities in two, and only nonclonal single-cell abnormalities in one. An extra chromosome 3, seen in four patients, was clonal in two and nonclonal in the two others. Cells with +5, +15, +19, +21, +22 were seen in two patients. All patients had 50% or more normal dividing cells in their LN. The mosaicism of unrelated abnormal cells in their LN. The mosaicism of unrelated abnormal karyotypes that was seen in four patients suggests that this malignant tumor is not necessarily monoclonal in its early stages, but that one clone may be selected and predominate in the late stage. Because nonrandom acquired clonal chromosome abnormalities are a consistent feature of malignancies, our data suggest that AILD may be a malignant disease despite its original description as a benign proliferative process. Therefore, it may require aggressive chemotherapy.

Description: In a chromosome study in childhood T-cell leukemia/lymphoma, we found t(7;11)(q35;p13) in 2 patients, t(7;14) (q35;q11) in one patient, and t(7;14)(p15;q32) in 1 patient. Southern blotting and in situ chromosomal hybridization studies in one patient with the t(7;11) demonstrated that both alleles of the T-cell antigen receptor beta- subunit gene (TCRB) were rearranged, and that one TCRB allele had relocated from 7q35 to the fusion point in band p13 of the involved chromosome 11 (11p-). These findings suggest that juxtaposition of TCRB with the putative oncogene tcl-2 located in band 11p13 may be a critical step toward development of this T-cell leukemia/lymphoma. In the other two translocations, all breakpoints were sites for lymphocyte function genes, ie, 7q35 for TCRB, 14q11 for T-cell antigen receptor alpha-subunit gene (TCRA), 7p15 for T-cell antigen receptor alpha- subunit gene (TCRG), and 14q32 for immunoglobulin heavy-chain gene (IGH). Thus, the findings in these cases allow us to expand the above hypothesis and propose that the juxtaposition of TCRB or TCRG with tcl- 2, TCRA, or IGH through chromosomal translocation may activate a mechanism for the genesis of T-cell leukemia/lymphoma with these chromosome translocations.

Description: Differentiation inhibitory factor (nm23 protein) inhibited the induction of differentiation of mouse myeloid leukemia M1 and WEHI-3BD+ and human erythroleukemia HEL, KU812, and K562 cells. Block of differentiation may be associated with the aggressive behavior of leukemia. To examine the role of nm23 in human myeloid leukemia, we investigated the relative levels of nm23-H1, nm23-H2, and c-myc transcripts in 42 patients with acute myelogenous leukemia (AML), and in 5 with chronic myelogenous leukemia at chronic phase by reverse transcriptase polymerase chain reaction. The expression of nm23-H1 and -H2 but not of c-myc in AML was significantly higher than that in normal blood cells. Among AMLs, acute monocytic leukemia (presentation with AML-M5 morphology) was especially associated with elevated nm23-H1 and -H2 mRNA levels. On the other hand, the elevated levels of c-myc expression in AML-M5 were less evident. An analysis of correlation between nm23 expression and clinicopathological parameters showed that resistance to initial chemotherapy is associated with increased nm23-H1 mRNA levels and that a high initial white blood cell count is associated with increased nm23-H2 mRNA levels. Elevated nm23-H1 mRNA levels were associated with significantly reduced the overall survival of AML, especially of AML-M5 patients. The present results indicate that nm23-H1 and -H2 are overexpressed in AML and especially nm23-H1 gene expression predicts the prognosis of AML, especially of AML-M5.

Description: The chromosomal translocation, t(8;21), is found frequently in acute myeloid leukemia (AML) with maturation (FAB-M2). We have previously mapped the translocation breakpoints of t(8;21) in a specific intron of the AML1 gene on chromosome 21. In this study, we cloned cDNAs synthesized from a cell line carrying t(8;21) by reverse transcription polymerase chain reaction (RT-PCR) using an AML1-specific primer. The analysis of the cDNAs structure has led to the identification of the fusion of AML1 with a gene named MTG8 on chromosome 8, which seems to be identical to ETO. Northern analysis using MTG8 (ETO) probes detected 7.8-kb and 6.2-kb RNAs and several minor RNAs in the cell line with t(8;21), but failed to detect any transcripts in a cell line without t(8;21). A set of primers were designed to detect the AML1/MTG8(ETO) fusion by PCR. The PCR amplified identical products in all 6 patients and one cell line with t(8;21), suggesting that the AML1/MTG8(ETO) fusion is a constant feature associated with t(8;21) and the junctions of the AML1/MTG8(ETO) fusion are restricted in a unique site. Because the PCR detection of the AML1/MTG8(ETO) fusion at the RNA level is highly sensitive, it can be used as a sensitive method for diagnosis and detection of minimal residual disease in t(8;21) leukemia.

Description: We studied the clinical, morphological, and immunologic characteristics of 11 patients with 11q translocation-associated acute leukemia. There were three patients with t(9;11)(p22;q23), one with a variant of the t(9;11), three with t(11;19)(q23;p13), two with t(1;11)(p32;q23), one with t(10;11)(p15;q22or23), and one with t(11;17) (q23;q25). The breakpoints in chromosome 11 clustered in band q23. The morphological feature was FAB-M5 in two patients, FAB-M2 in one, FAB-L1 in six, and lymphoblastic lymphoma in one. The remaining patient underwent morphological changes from FAB-L1 seen at the time of diagnosis to M5b at relapse. Immunologic marker studies in ten patients revealed that one had T cell type; another pre-B cell type; three CALLA- Ia- non-T, non-B type; two CAL-LA- Ia+ non-T, non-B type; two monocytic type (positive Fc-receptor); and the remaining one underwent phenotypic changes from CALLA+ Ia+ non-T, non-B type to monocytic type. The patients were usually young; five were under 1 year and two were 9 and 13 years. Hyperleukocytosis was observed in eight of the ten patients with acute leukemia, and two of the eight died of intracranial hemorrhage within two days of admission, associated with disseminated intravascular coagulation. These findings indicate that leukemia with the 11q23 translocation share certain characteristics in common, irrespective of the recipient chromosome, even though the latter may have some influence on the morphological and immunologic phenotype. Our data provide a hypothesis that multipotent stem cells are involved in the genesis of the 11q translocation-associated leukemia.