ider(17)(q10)t(15;17) associated with relapse and poor prognosis in a pediatric patient with acute promyelocytic leukemia

Although acute promyelocytic leukemia (APL) has been regarded as a serious medical emergency associated with disseminated intravascular coagulopathy or subsequent mortality, it is now considered a curable leukemia that is particularly sensitive to treatment with all-trans retinoic acid combined with chemotherapy. However, it is not clear whether additional chromosomal abnormalities in APL patients directly influence the prognosis or treatment response. ider(17)(q10)t(15;17)(q22;q21) has mostly been reported in adult APL patients, and only three cases of pediatric APL associated with ider(17)(q10)t(15;17) showing poor prognosis have been described in the literature. Here, we report the close follow-up (clinical and laboratory) data of a pediatric APL case associated with ider(17)(q10)t(15;17). This patient had APL relapse from the same clone 15 months after morphological remission. Furthermore, despite subsequent chemotherapy, the patient died 16 months after the initial APL diagnosis. Although based on a limited amount of data (four pediatric APL cases), such results in pediatric APL patients may provide important insight into the relationship between ider(17)(q10)t(15;17) and poor prognosis. However, further well-designed case-control studies are necessary to determine the treatment response and prognosis in pediatric or adult APL patients with ider(17)(q10)t(15;17).     

Two cases of acute promyelocytic leukemia with variant translocations: the importance of chromosome No. 17 abnormality

Two patients with acute promyelocytic leukemia (APL) were found to have chromosomal translocations in their leukemic cells; one had a 46,XX,t(7;17)(q36;q22) and another a 46,XY,t(1;17)(p36;q21) karyotype. These two cases of APL seem to be the first involving variant translocations instead of the standard t(15q+; 17q-) translocation. The present cases strongly suggest that the rearrangement of chromosome #17, which occurs in bands of the q21-22 region of the long arm, is crucially important in the pathogenesis of APL.     

Two cases of acute myeloid leukemia with t(11;17) associated with varying morphology and immunophenotype: rearrangement of the MLL gene and a region proximal to the RARalpha gene

This report describes 2 cases of acute myeloid leukemia (AML), which based on the WHO classification would be classified as AML with an 11q23 (MLL) abnormality, but with contrasting morphologic and immunophenotypic profiles. One case had monocytic features (morphologically and immunophenotypically) with a t(11;17)(q23;q21), a previously identified variant translocation in acute promyelocytic leukemia (APL). The second case had morphologic and immunophenotypic features of APL associated with a t(11;17)(q23;q25). In both cases, fluorescence-in-situ hybridization (FISH) analysis demonstrated that the 11q23 breakpoint involved the MLL gene, but RARalpha was not involved in the 17q breakpoints. These cases illustrate the importance of FISH analysis to confirm the presence of a particular recurring rearrangement.     

A new variant translocation 11;17 in a patient with acute promyelocytic leukemia together with t(7;12)

Bone marrow cells from the majority of patients with acute promyelocytic leukemia (APL) are characterized by t(15;17)(q22;q11-12). At least 12 variant translocations have both also reported, and in each case, either abnormal chromosome 15 or del(17q) or both were involved in complex rearrangements. We report a patient with APL showing two translocations without apparent involvement of chromosome 15 and without del(17q). The karyotype was 46,XY,t(7;12)(p15;p13),t(11;17)(q13;q12). Rearrangement involving t(11;17) is probably associated with APL, while t(7;12) appears to be therapy related.     

Atypical blasts and bone marrow necrosis associated with near-triploid relapse of acute promyelocytic leukemia after arsenic trioxide treatment

The pathologic features of acute promyelocytic leukemia (APL) with t(15;17)(q22;q21) are highly characteristic, which with few exceptions enable a firm diagnosis to be made on morphologic grounds. An APL patient in first relapse presented with large, bizarre circulating blasts and bone marrow necrosis 2 weeks after chemotherapy consolidation for an arsenic trioxide-induced remission. Although a morphologic diagnosis could not be reached, cytogenetic investigations showed a near-triploid clone with t(15;17), confirming APL in second relapse. This case showed that clonal evolution with additional karyotypic aberrations might alter the blast morphology and pathologic features in APL.     

Derivative (7)t(7;8)(q34;q21). a new additional cytogenetic abnormality in acute promyelocytic leukemia

Cytogenetic abnormalities in acute myelocytic leukemia (AML) have been identified as one of the most important prognostic factors. The t(15;17) is associated with high rates of complete remission and event-free survival. Secondary chromosomal changes are also present in approximately one third of patients with newly diagnosed acute promyelocytic leukemia (APL). Indeed, the gain of whole chromosome 8 may be involved in the course of APL under C-MYC gene dosage effect theory. Complete or partial loss of the long arm of chromosome 7 region has been recognized in preleukemic myelodysplasia or unfavorable AML. We report here two original APL cases in which a new additional chromosomal abnormality, der(7)t(7;8)(q34;q21), is associated with the t(15;17)(q22;q21). This recurrent abnormality results in a partial loss of 7q associated with a partial 8q trisomy. As the 7q and 8q breakpoints were similar in both cases, the involvement of these critical regions in the pathogenesis and outcome of APL disease has to be determined.     

Second relapse of acute promyelocytic leukemia (ANLL-M3) with t(15;17) and t(1;3)(p36;q21).

We describe herein a patient with acute promyelocytic leukemia (APL)-(ANLL-M3) whose bone marrow cells in the second relapse showed t(1;3)(p36;q21) together with t(15;17) (q22;q11-q12). Although a total of 21 patients with t(1;3) have been reported so far, among which three cases with de novo acute nonlymphocytic leukemia were included, our patient is the first case with APL. The hematologic findings in our case confirmed the previous observations that this anomaly is associated with relatively high platelet count and the multi-myeloid lineage involvement of leukemic cells. Our patient responded well to chemotherapy and achieved first and second remission with 42 months of total survival, contrary to our expectation that patients with this anomaly have a poor prognosis.     

A new variant t(6;15;17)(q25;q22;q21) in acute promyelocytic leukemia: fluorescence in situ hybridization confirmation

Acute promyelocytic leukemia (APL) is characterized by the t(15;17)(q22;q21), which results in the fusion of the promyelocytic leukemia (PML) gene at 15q22 with the retinoic acid alpha-receptor (RARalpha) at 17q21. The 2 chimeric genes PML/RARalpha and RARalpha/PML are thought to play a role in leukemogenesis. We report a case of APL in a patient carrying an apparently complex variant translocation identified as t(6;15;17) by R-banding and whole chromosome 15 and 17 painting. However, FISH analysis with a PML/RARalpha dual-color kit showed a more complex translocation, resulting presumably from a two-step rearrangement, with PML-RARalpha fusion gene located as expected on the der(15) but the residual 5'-RARalpha signal located on the der(6). The patient achieved complete remission with all-trans retinoic acid treatment associated with chemotherapy. This case illustrates the usefulness of combined cytogenetics, FISH, and molecular biology to evidence the PML/RARalpha fusion gene in complex cases.     

Flow cytometry rapidly identifies all acute promyelocytic leukemias with high specificity independent of underlying cytogenetic abnormalities

Acute promyelocytic leukemia (APL) is a highly aggressive disease requiring prompt diagnosis and specific early intervention. Immunophenotyping by flow cytometry (FCM) facilitates a rapid diagnosis, but commonly used criteria are neither sufficiently sensitive nor specific. With an antibody panel for diagnostic screening in routine practice, we found all 149 APL cases in this study exhibited a unique immunophenotypic profile, ie, a characteristic CD11b- myeloid population and absent CD11c expression in all myeloid populations; 96.6% of cases also lacked HLA-DR expression. These distinctive features allowed recognition of all unusual cases phenotypically resembling the regular myeloblasts (CD34+/HLA-DR+) or granulocytes (CD117-/CD34-/HLA-DR-). FCM effectively identified all 19 APL cases with variant translocations, including cases with a normal karyotype due to a cryptic submicroscopic t(15;17)(q22;q21), t(11;17)(q23;q21) that escaped the detection by fluorescence in situ hybridization for t(15;17) and der(15)ider(17)(q10) that lacked a simple reciprocal t(15;17). When APL-associated profiles were validated against 107 AML cases of non-APL subtypes, including 51 HLA-DR- cases, the diagnostic specificity and positive predictive value were 98%. FCM effectively provides independent detection of APL during diagnostic workup and harmonizes with the subsequent molecular cytogenetic diagnosis.     

Deletion of MYC and presence of double minutes with MYC amplification in a morphologic acute promyelocytic leukemia-like case lacking RARA rearrangement: could early exclusion of double-minute chromosomes be a prognostic factor?

Gene amplification on double minutes is rarely found in acute myeloid leukemia (AML) and is often linked to poor prognosis. It is often associated with acute myeloid leukemia with differentiation (AML-M2) and is rarely reported in acute promyelocytic leukemia (APL), which is characterized in the vast majority of cases by the reciprocal t(15;17)(q22;q21) with resultant translation of an abnormal PML-RARA fusion protein. Most of the rare cases of APL that lack this translocation have a demonstrable RARA breakpoint. We report on a morphologic APL-like case lacking t(15;17) and the RARA breakpoint and also has the deletion MYC of 8q24 associated with the occurrence of MYC amplification on double-minute chromosomes (dmin). Excessive exclusion of dmin was observed at the initial diagnosis. These findings are compared to the few cases previously reported in the literature.     

Chronic myelomonocytic leukemia with trisomy 8 and a related clone with trisomy 8 and t(15;17)

We describe a patient with chronic myelomonocytic leukemia who showed trisomy 8 in 100% of his bone marrow metaphases. Of interest was the finding that 20% of the Giemsa-banded metaphases also showed t(15;17)(q22;q21), with breakpoints indistinguishable from those seen in cases of acute progranulocytic leukemia (APL). The patient showed no morphologic or clinical evidence of APL, and he died after 6 months, with no evidence that the disease had progressed to acute leukemia. Although cytogenetically the breakpoints appeared to be the same as those in APL, we suspect that this patient's translocation may have differed at the molecular level from the t(15;17) commonly seen in APL.     

Tetraploid acute promyelocytic leukemia with double t(15;17) and PML/RARA rearrangements detected by fluorescence in situ hybridization analysis

Acute promyelocytic leukemia (APL) is characterized by a serious hemorrhagic syndrome, unique morphologic findings, and its response to retinoids. Tetraploidy is a very rare chromosomal abnormality in acute myelocytic leukemia. This report presents a unique case of APL with a tetraploid clone characterized by two t(15;17) without other chromosomal changes, as well as PML/RARA rearrangements confirmed fluorescence in situ hybridization. The morphology of the blast cells was that of the classic M3 subtype, but the mean blast size exceeded that of control APL cases with diploidy. A chromosomal study revealed a 92,XXXX,t(15;17)(q22;q21)x2 karyotype in all 20 metaphase spreads. Despite all-trans-retinoic acid (ATRA) treatment and chemotherapy, leukemic cells persisted in the blood, and the patient died of an intracranial hemorrhage on the 16th day after admission.     

Rearrangements of the RARA and PML genes in a cytogenetic variant of acute promyelocytic leukemia

Acute promyelocytic leukemia (APL) is usually associated with the translocation t(15;17)(q22;q12-21), which disrupts the retinoic acid receptor alpha (RARA) gene on chromosome 17 and the PML gene on chromosome 15. We report a patient with typical APL without the common t(15;17). Cytogenetic studies demonstrated a normal appearance of chromosomes 15, while a small marker seemed to be an i(17q—). Molecular analysis showed RARA and PML rearrangements, suggesting that the chromosome abnormality corresponded to a variant translocation. © 1993 Wiley-Liss, Inc.     

Cytogenetic findings in patients with acute promyelocytic leukemia and a case of CML blast crisis with promyelocytic proliferation

Nineteen patients with acute promyelocytic leukemia (APL) and one with promyelocytic blast crisis were studied by a methotrexate cell synchronization technique and by 24-hour short-term culture. Nineteen cases of APL included two cases of the microgranular variant (M3V). Except in one case of M3V, t(15;17) was detected in all patients. The breakpoints were determined as 15q22 and 17q12-21. A chronic myeloid leukemia (CML) blast crisis patient with high promyelocyte count also had a t(15;17) as well as a masked Ph chromosome. Other abnormalities, such as +8,del(7q) and an i(17q), were also observed in some patients. Our studies have indicated that 1) the translocation (15;17), characteristic of APL, was present in our population in almost all patients; 2) the presence of an identical abnormality in a promyelocytic CML blast crisis supported and confirmed the phenomenon of association of specific chromosome change with target cell type; and 3) the precise localization of breakpoints on chromosome 17 is still difficult to determine. The identification of as yet unknown genes at region 17q11-q21 and their subsequent translocation on chromosome 15 will help in assigning a precise position to these breakpoints.