Acute myelomonocytic leukemia with inv(16)(p13q22) complicating Philadelphia chromosome positive chronic myeloid leukemia.

The reciprocal translocation (9;22)(q34;q11) is highly characteristic of chronic myeloid leukemia (CML) and the pericentric inversion inv(16)(p13q22) is almost only found in acute nonlymphocytic leukemia of the myelomonocytic subtype (ANLL M4). Only twice before have an inv(16) and a t(9;22) been found in the same cells, and both times the patients seemed to have de novo ANLL M4. We describe the case of a 21-year-old man who in July 1986 presented with a clinically and hematologically classic chronic phase CML. Treatment with busulfan led to no improvement; instead in September 1986 he developed blast crisis with ANLL M4Eo morphology. He was now cytogenetically examined and the karyotype 45,X,-Y,t(9;22)(q34;q11),inv(16)(p13q22) was found. Southern blot analysis of the bone marrow DNA sampled at this time revealed a standard rearrangement in the 3' end of the M-bcr. Intensive cytostatic treatment caused cytopenia followed by complete hematologic, clinical, and cytogenetic reversal to chronic phase CML, so that in January 1987 the bone marrow karyotype was 46,XY,t(9;22)(q34;q11). Persistent splenomegaly was treated with splenectomy, and a chloroma of the skin was removed by irradiation. In March 1987 he received an allogeneic bone marrow transplant. Since then his only medical problem has been mild graft-versus-host disease; he is well and is working full time as a blacksmith.     

Chromosome studies on 30 Chinese patients with acute nonlymphocytic leukemia in Taiwan

Cytogenetic studies were performed on 32 consecutive Chinese patients with de novo acute nonlymphocytic leukemia (ANLL) in Taiwan. Of the 30 patients with adequate specimens, 20(66%) had clonal chromosome abnormalities. Structural rearrangements were detected in 18 of them. Seven (four were children) of the 16 patients with M2 ANLL had t(8;21). All six patients with acute promyelocytic leukemia (APL; M3 subtype) had t(15;17). Two patients with M4 type leukemia and abnormal bone marrow eosinophils had inv(16)(p13q22). Another M4 patient with a mild increase of morphologically normal eosinophils in the bone marrow had an abnormal chromosome #16, t(1;16)(q21;p13) in which 16q22 was not involved. One patient with M5 ANLL had t(9;11). Only two patients had a numerical change as the sole abnormality. None of the patients had loss or deletion of chromosome #5 or loss of chromosome #7, and only one had a deletion of 7q. This study revealed a high incidence of t(8;21), t(15;17), and a low incidence of -5/5q- or -7/7q- in Chinese patients with ANLL.     

Coexistence of inversion 16 and the Philadelphia chromosome in acute and chronic myeloid leukemias : report of six cases and review of literature

We report 5 cases of chronic myelogenous leukemia (CML) and 1 case of acute myeloid leukemia (AML) with the dual presence of t(9;22) and inv(16). The 6 patients were 5 men and 1 woman with a median age of 42.5 years. All cases were BCR-ABL+ with p210 products detected in all CML cases and a p190 product detected in the AML case. An increase in bone marrow eosinophils was detected in 3 of 5 cases, and abnormal eosinophils were identified in these 3 cases. The CBFbeta-MYH11 fusion gene was confirmed in all 3 CML cases and the 1 AML case tested, and this correlated with the presence of abnormal eosinophils with coarse basophilic granules. Of 5 patients with CML, 4 had a rapid transformation to myeloid accelerated phase of blast crisis. The coexistence of t(9;22) and inv(16) in CML seems to correlate with more rapid transformation.     

Inversion of chromosome 16 with the Philadelphia chromosome in acute myelomonocytic leukemia with eosinophilia. Report of two cases.

Two cases are described with the rare combination of inv(16)(p13q22), strongly associated with acute myelomonocytic leukemia with eosinophilia, M4Eo, and the Philadelphia translocation, t(9;22)(q34;q11), hallmark of chronic myeloid leukemia (CML) and rarely found, (less than 1%), in acute nonlymphocytic leukemia. The patients were: case 1, a 9-year-old girl presenting with a white blood cell count (WBC) 42 x 10(9)/L with 32% blasts and bone marrow with blasts and eosinophil precursors consistent with M4Eo, and case 2, a 25-year-old man with WBC 34.7 x 10(9)/L with 13% blasts and bone marrow with features of M4Eo and basophilia. Both patients achieved remission but died following bone marrow transplantation in first remission (case 1) or in relapse (case 2). Cytogenetic findings were: case 1, at diagnosis, 46,XX,inv(16)(p13q22)(21)/46,XX,t(9;22) (q34;q11),inv(16)(8)/46,XX(10), and case 2, at diagnosis, 46,XY,t(9;22) (q34;q11),inv(16)(p13q22) (16) and in remission, 46,XY,t(9;22)(q34;q11) (1)/46,XY (24). Investigation of the breakpoint on 22 in case 1 with Southern blotting and the polymerase chain reaction demonstrated the presence of a p190 mRNA and a breakpoint typical of acute leukemia. Thus a diagnosis of M4Eo was supported by clinical and cytogenetic sequelae in each case; the Ph in case 1 was apparently secondary to inv(16), in case 2 the Ph probably preceded inv(16) in the etiology of the leukemia.     

t(8;21)(q22;q22) in blast phase of chronic myelogenous leukemia

The blast phase of chronic myelogenous leukemia (CML) frequently is associated with cytogenetic evidence of clonal evolution, defined as chromosomal aberrations in addition to the t(9;22)(q34;q11.2). We identified the t(8;21)(q22;q22) and other cytogenetic abnormalities by conventional cytogenetics and fluorescence in situ hybridization in 2 patients with t(9;22)-positive CML at the time of blast phase. The t(8;21), which typically is associated with a distinct subtype of de novo acute myeloid leukemia (AML) carrying the aml1/eto fusion gene, was accompanied by increased bone marrow myeloblasts (33%) in case 1 and extramedullary myeloid sarcoma in case 2, suggesting its possible role in disease progression. In case 1, the leukemic cells in aspirate smears had salmon-colored cytoplasmic granules, and immunophenotypic studies showed that the blasts expressed CD19. These findings suggest that the pathologic features of blast phase CML with the t(8;21) resemble those of de novo AML with the t(8;21).     

A unique structural abnormality of chromosome 16 resulting in a CBF beta-MYH11 fusion transcript in a patient with acute myeloid leukemia, FAB M4

A 43-year-old female with a peripheral white cell count of 118.0 x 10(9)/L and 96% blasts was diagnosed with acute myeloid leukemia (AML), FAB M4. Cytogenetics, performed on a bone marrow sample, revealed the following abnormal karyotype: 46,XX,ins(16)(q22p13.1p13. 3). Fluorescence in situ hybridization (FISH) confirmed the inter-arm insertion using a probe for 16p. The result of this structural rearrangement was the fusion of CBF beta to MYH11 seen commonly in inv(16)(p13q22). The patient commenced high-dose intensive combination chemotherapy (big ICE; Idarubicin, Cytarabine, and Etopiside). Five days post chemotherapy, she developed febrile neutropenia. Despite broad spectrum intravenous antibiotics and antifungal therapy, the patient died at day nine post chemotherapy. This case demonstrates a previously unreported structural abnormality of chromosome 16 in a patient with AML M4, which represents a third mechanism to inv(16)(p13q22) and t(16;16)(p13q22) in producing the CBF beta-MYH11 fusion. CBF beta-MYH11 fusions masked by cryptic translocations at the cytogenetic level have been detected by FISH and PCR techniques. Due to the improved prognosis associated with CBF beta-MYH11 fusions compared to the standard risk group for AML, its detection remains important.     

Comparative analysis of genes regulated in acute myelomonocytic leukemia with and without inv(16)(p13q22) using microarray techniques, real-time PCR, immunohistochemistry, and flow cytometry immunophenotyping.

Acute myeloid leukemia with inv(16)(p13q22), also known as M4Eo, is a distinct type of leukemia with characteristic clinicopathologic and cytogenetic features. Patients with M4Eo have monocytosis, high blast counts, and abnormal bone marrow eosinophils that contain large basophilic granules. The inv(16)(p13q22) or, less commonly, the t(16;16)(p13;q22) causes fusion of the CBFbeta gene at 16q22 and the MYH11 gene at 16p13, creating the novel chimeric protein CBFbeta-MYH11. To understand the underlying molecular mechanisms unique to M4Eo biology, we determined the gene expression profile of M4Eo cases by using cDNA and long oligonucleotide microarrays. Cases of acute myelomonocytic leukemia without CBFbeta-MYH11 (M4) acted as our control. We found that in the gene expression profile of M4Eo, NF-kappaB activators and inhibitors were upregulated and downregulated, respectively, suggesting that the NF-kappaB signaling pathway is activated at a higher level in M4Eo than in acute myelomonocytic leukemia M4. In addition, the gene expression profile of M4Eo indicates high cell proliferation and low apoptosis. We used real-time PCR, immunohistochemistry, and flow cytometry immunophenotyping to confirm some of our microarray data. These findings most likely represent the functional consequences of the abnormal chimeric protein CBFbeta-MYH11, which is unique to this disease, and suggest that NF-kappaB is a potential therapeutic target for treating M4Eo patients.     

Gain of multiple copies of the CBFB gene: a new genetic aberration in a case of granulocytic sarcoma

Granulocytic sarcomas (GS) are tumor masses of immature myeloid cells presenting at an extramedullary site, mainly the skin, bone, and lymph node. They are often associated with acute myeloid leukemia (AML) with monoblastic or myelomonocytic differentiation, including either AML M2 with t(8;21)(q22;q22) or AML M4Eo with inv(16)(p13q22). We present a case diagnosed with GS associated with AML M4 that presented a normal karyotype with conventional cytogenetic analysis. Although the myeloblasts did not show the inv(16)(p13q22) (CBFB/MYH11), a gain of multiple copies of the CBFB gene was detected with fluorescence in situ hybridization analysis. To our knowledge, no cases with this rare genetic anomaly have been previously described.     

Nonrandom additional chromosome changes in acute nonlymphocytic leukemia with inv(16)(p13q22)

Five patients with acute nonlymphocytic leukemia and inv(16)(p13q22), all with additional chromosome changes, are reported. Three were diagnosed as having acute myelomonocytic leukemia (FAB-M4), and the other two as having acute monocytic leukemia (FAB-M5b). All five patients had abnormal eosinophils in the bone marrow at diagnosis. Two had a deletion of the long arm of chromosome #7, del(7)(q31), and a trisomy of chromosome #22. These changes have been reported frequently in acute nonlymphocytic leukemia with inv(16), but are extremely rare in leukemias with other specific rearrangements including t(9;22), t(8;21), and t(15;17). Our findings and review of the literature indicate that inv(16) is observed not only in acute myelomonocytic leukemia but also in acute monocytic leukemia, and that del(7q) and +22 are nonrandomly associated with inv(16) as additional abnormalities. No significant differences in the clinical features seem to exist between the patients with only inv(16) and those with inv(16) and additional chromosome changes, except for the lower white blood cell count in the latter group.     

The predictive value of initial cytogenetic studies in 148 adults with acute nonlymphocytic leukemia: a 12-year study (1970-1982)

When leukemic blood or marrow specimens from 148 adults with newly diagnosed acute nonlymphocytic leukemia (ANLL) were studied with chromosome banding techniques, 79 were found to have clonal abnormalities. Among 130 treated patients, the 53 with initially normal karyotypes had a significantly longer survival rate than the 16 in whom no normal metaphases were observed (p = 0.02). The 55 patients with both normal and abnormal metaphase cells had an intermediate survival. Once a complete remission had been attained, however, there was no significant difference in median survival between those patients with entirely normal karyotypes and those with abnormal karyotypes. Among the various FAB morphologic subsets of ANLL, the differences in complete remission rate and overall survival between the various cytogenetic subsets were greatest in acute myelogenous leukemia (AML, M1 + M2). The presence of an abnormal clone was a more important predictor of clinical outcome (p = 0.02) than the presence of normal stem cell clones. Aneuploidy alone (hyperdiploidy or hypodiploidy) was not of predictive value, indicating that the use of banding techniques to identify structural rearrangements in pseudodiploid cells was essential. Clonal chromosomal abnormalities were nonrandom and acquired, and specific abnormalities were closely associated with specific clinical-pathologic subsets of ANLL. All 13 patients with acute promyelocytic leukemia and adequate cytogenetic specimens had t(15;17); this translocation was not found in any other subset of ANLL. Six patients with AML (M2) had t(8;21) or a variant of this rearrangement. Seven patients had inv(16)(p13q22) associated with acute myelomonocytic leukemia (AMMoL, M4) and abnormal marrow eosinophils. Two patients had ins(3;3) and thrombocytosis. Four patients had a translocation involving 11q, but none of these had acute monocytic leukemia (AMoL, M5); no patient had del(11q).     

Myelodysplastic syndrome with inv(3)(q21q26.2) or t(3;3)(q21;q26.2) has a high risk for progression to acute myeloid leukemia

Acute myeloid leukemia (AML) with inv(3) (q21q26.2) or t(3;3)(q21;q26.2) is a distinct subtype in the World Health Organization classification. The natural history of myelodysplastic syndrome (MDS) associated with these cytogenetic aberrations is poorly understood. We studied 17 MDS (11 de novo and 6 therapy related) and 3 chronic myelomonocytic leukemia (CMML) cases associated with inv(3) (q21q26.2) or t(3;3)(q21;q26.2). The de novo cases were further classified as refractory cytopenia with multilineage dysplasia (n = 8) and refractory anemia with excess blasts (n = 3). Isolated inv(3)/t(3;3) was identified in 4 cases, whereas -7/7q (n = 13) and -5/5q (n = 6) were common additional aberrations. Nineteen patients died, including 13 in whom the disease progressed to AML after a median of 7 months. Median survival for patients with de novo disease was similar to that for patients with therapy-related MDS (13 vs 17.5 months). MDS or CMML with inv(3)/t(3;3) are aggressive diseases with a high risk of progression to AML.     

Association of an inversion of chromosome 16 with abnormal marrow eosinophils in acute myelomonocytic leukemia. A unique cytogenetic-clinicopathological association

We identified 18 patients with an inversion of chromosome 16, inv(16)(p13q22), among 308 patients with newly diagnosed acute nonlymphocytic leukemia. Each of these 18 patients had acute myelomonocytic leukemia (M4 subtype) and eosinophils with distinctly abnormal morphology, cytochemical staining, and ultrastructure. These eosinophils constituted from 1 to 33 per cent of the nucleated marrow cells. In our series, every patient with acute myelomonocytic leukemia and abnormal eosinophils also had an abnormal chromosome 16. This subgroup of M4 patients had a good response to intensive therapy designed to induce remission; 13 of 17 treated patients entered a complete remission, and 10 remain in first remission. Thus, patients with an inversion of chromosome 16 appear to represent a unique cytogenetic-clinicopathological subtype of acute nonlymphocytic leukemia with a favorable prognosis.     

Deletion of CBFB in a patient with acute myelomonocytic leukemia (AML M4Eo) and inversion 16

Acute myelomonocytic leukemia with bone marrow eosinophilia (AML M4Eo) is a subtype of AML with distinct morphological features. Inversion (16)(p13.1q22), t(16;16)(p13.1;q22), and del(16)(q22) are nonrandom abnormalities associated with AML M4Eo and a favorable prognosis, compared with the standard risk group for AML. Deletions of the proximal region of the MYH11 gene located at 16p13.1 have been detected in about 20% of patients with inv(16), with an undetermined effect on patient survival. We present the case of a patient with AML M4Eo and inversion 16 with a distal deletion of the CBFB gene at 16q22 detected with fluorescence in situ hybridization. To our knowledge, only one previous report of a similar deletion has appeared in the literature.     

Inversion of chromosome 3 in a case of chronic myelogenous leukemia with abnormal thrombopoiesis

A patient with chronic myelogenous leukemia (CML) associated with a remarkable increase of micromegakaryocytes in bone marrow was revealed to have an abnormality of a long arm of chromosome #3, i.e., inv(3)(q21q26), in addition to a complex Ph translocation: t(9;22;15)(q34;q11;q22). Although several cases of acute leukemia with inv(3)(q21q26) and abnormal megakaryocytes have been reported, this is the first case in which the association of inv(3)(q21q26) with a megakaryocytic abnormality was observed in a patient with CML. Our findings suggest that this structural rearrangement may be more specifically associated with abnormal thrombopoiesis than are other structural anomalies of 3q.     

Deletion of 16q11 is a recurrent cytogenetic aberration in acute myeloblastic leukemia during disease progression.

Abnormalities of chromosome 16 other than inv(16)(p13q22), t(16;16)(p13;q22), and del(16)(q22) have not been fully characterized in acute myeloblastic leukemia (AML) and myelodysplastic syndrome (MDS). We report here the first case of AML with del(16)(q11) as a sole abnormality. A 53-year-old woman was initially diagnosed as MDS, refractory anemia with excess of blasts in transformation with normal karyotype. After sixteen months, the disease progressed to overt AML-M1. Myeloblasts were positive for CD13, CD33, and CD34, but negative for HLA-DR. Chromosome analyses of the bone marrow cells showed 46,XX,del(16)(q11) in all metaphase spreads. Multicolor spectral karyotyping also confirmed that del(16)(q11) was not derived from a cryptic translocation, but a simple deletion. Our results, together with three previously reported cases, suggest that del(16)(q11) may be one of the recurrent aberrations in AML and that it could be associated with clonal evolution or disease progression.     

Dysplasia and high proliferation rate are common in acute myeloid leukemia with inv(16)(p13q22)

Acute myeloid leukemia (AML) with inv(16)(p13q22), also known as M4Eo, is a distinct type of AML with a favorable prognosis associated with abnormal bone marrow eosinophils. We reviewed the morphologic findings of archival bone marrow specimens with M4Eo, specifically assessing for dysplasia, and performed immunohistochemical studies to assess the growth fraction using the MIB-1 (Ki-67) antibody. We also assessed the apoptotic rate by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-nick end labeling. All assessable cases had more than 10% dysplastic forms in at least 1 lineage. Seventeen cases had 10% or more dysplastic forms, and 3 cases had more than 50% dysplastic forms in at least 2 lineages. Immunoreactivity for Ki-67 was higher in M4Eo than in other AML types (P = .000). The apoptotic rate in M4Eo was similar to other AML types (P = .724). Our data show that dysplasia is a prominent feature, but not a prognostic indicator, in M4Eo. M4Eo is associated with a significantly higher proliferation rate than other AML types.     

A myelodysplastic syndrome with marrow eosinophilia terminating in acute nonlymphocytic leukemia, associated with an abnormal chromosome 16

A patient presented with a myelodysplastic syndrome and bone marrow eosinophilia that evolved six months later into an acute nonlymphocytic leukemia (ANLL). Cytogenetic analyses of the bone marrow revealed 86% of the metaphases with 45,X-Y,inv(16)(p13;q22),t(11;17) (q11;q25),del(21)(q13) and 14% of the metaphases with the same abnormalities but with a Y chromosome. The association of ANLL, bone marrow eosinophilia, and abnormal chromosome 16 has previously been reported and has been suggested to have a favorable prognosis. Our patient is unique in that ANLL was preceded by a preleukemic phase associated with bone marrow eosinophilia. When complete remission was achieved, the bone marrow cytogenetics returned to normal, and the eosinophilia disappeared.