The prognostic implications of tetraploidy/near-Tetraploidy in acute myeloid leukemia: a case series and systematic review of the literature.

The prognostic significance and optimal management of tetraploidy/near-tetraploidy acute myeloid leukemia (T/NT AML) remains unclear given its limited data. This is especially true after factoring in additional chromosomal alterations, which carry their own prognostic weight. Here, we analyze 128 cases of T/NT in AML from the literature along with two additional cases, which is the largest review of this subject to date. Based on our retrospective analysis, we found that regardless of the risk status attributed to cytogenetics, the prognosis of tetraploid or near-tetraploid AML is dismal and should be incorporated within the unfavorable risk group. Complete remission is paramount to survival in this population. Specific induction protocols for high-risk AML appear to have higher rates of complete remission in the T/NT AML population. Moreover, longer overall survival can be achieved with chemotherapy followed by allogeneic stem cell transplantation at first complete remission.

Tetraploid/near-tetraploid acute promyelocytic leukaemia with double (15;17) translocation

@#A 57-year-old man presented with intermittent fever and bleeding following dental surgery. Peripheral smear and bone marrow aspirate exhibited unusually large and bizarre-looking abnormal cells which were found to be myeloblasts with aberrant CD56 and CD2 expression on immunophenotyping. Fluorescence in situ hybridization analysis revealed an extra RARA gene rearrangement. This finding correlated well with a near-tetraploid karyotype with double t(15;17)(q22;q21). Bcr-3 type PML/ RARA copies were identified in reverse transcriptase-polymerase chain reaction. The diagnosis of near-tetraploid acute promyelocytic leukaemia (APML) was established. The patient was treated with all-trans retinoic acid and idarubicin and six weeks later achieved complete remission. Tetraploid/ near-tetraploid APML is exceedingly rare. It is a distinct cytogenetic subgroup with unique clinical and biological features as highlighted by atypical morphology, frequent CD2 expression and association with the bcr-3 type PML/RARA fusion transcripts. Early recognition of this rare entity is essential for timely and appropriate treatment.

Near Tetraploidy Acute Myeloid Leukemia in Long-term Remission with Persistent Clonal Hematopoiesis with del(20)(q12q13).

Patients with near tetraploidy/tetraploidy (NT/T)-acute myeloid leukemia (AML) are rare and generally show poor survival. A 62-year-old man was referred to our hospital with pancytopenia. A bone marrow examination revealed the proliferation of extremely large blasts, and led to the diagnosis of AML M0. A cytogenetic analysis showed an NT-karyotype of 91, XXYY, -5, add(18)(p21),del(20)(q12q13) ×2. Complete remission was achieved with single remission induction chemotherapy. Although consolidation chemotherapies were not available because of his critical condition, he remained in remission and survived for more than 40 months without cytopenia. However, repeated bone marrow examinations showed persistent clonal hematopoiesis with del(20)(q12q13) without apparent myelodysplasia.

Mixed phenotype acute leukemia, B/myeloid, NOS with near-tetraploidy: a case report.

Acute leukemia in adults is usually associated with a myeloid phenotype, and less commonly presents as an acute lymphocytic leukemia. Rarely, the leukemic blast cells express more than one lineage phenotype and satisfy the diagnostic criteria for an acute leukemia of ambiguous lineage (ALAL), further subclassified as mixed phenotype acute leukemia (MPAL). Near-tetraploidy is an unusual presentation of acute leukemia where the blasts contain 80-104 chromosomes. More commonly associated with acute lymphocytic leukemia, near-tetraploidy has been described in only a limited number of cases of acute myeloid leukemias, and near-tetraploid ALAL is rare. We describe the first report of near-tetraploid MPAL, B/myeloid, not otherwise specified.

HIPK2 deficiency causes chromosomal instability by cytokinesis failure and increases tumorigenicity.

HIPK2, a cell fate decision kinase inactivated in several human cancers, is thought to exert its oncosuppressing activity through its p53-dependent and -independent apoptotic function. However, a HIPK2 role in cell proliferation has also been described. In particular, HIPK2 is required to complete cytokinesis and impaired HIPK2 expression results in cytokinesis failure and tetraploidization. Since tetraploidy may yield to aneuploidy and chromosomal instability (CIN), we asked whether unscheduled tetraploidy caused by loss of HIPK2 might contribute to tumorigenicity. Here, we show that, compared to Hipk2+/+ mouse embryo fibroblasts (MEFs), hipk2-null MEFs accumulate subtetraploid karyotypes and develop CIN. Accumulation of these defects inhibits proliferation and spontaneous immortalization of primary MEFs whereas increases tumorigenicity when MEFs are transformed by E1A and Harvey-Ras oncogenes. Upon mouse injection, E1A/Ras-transformed hipk2-null MEFs generate tumors with genetic alterations resembling those of human cancers derived by initial tetraploidization events, such as pancreatic adenocarcinoma. Thus, we evaluated HIPK2 expression in different stages of pancreatic transformation. Importantly, we found a significant correlation among reduced HIPK2 expression, high grade of malignancy, and high nuclear size, a marker of increased ploidy. Overall, these results indicate that HIPK2 acts as a caretaker gene, whose inactivation increases tumorigenicity and causes CIN by cytokinesis failure.

Chromosomal Abnormalities in Myelodysplastic Syndrome with Near-tetraploidy: A Case Report

Massive hyperdiploidy and tetraploidy are rare cytogenetic abnormalities in myelocytic malignancies, especially in myelodysplastic syndrome (MDS). These abnormalities are known to be associated with leukemogenesis, leukemic transformation and poor prognosis. We report here the first case of MDS with near-tetraploid cytogenetic abnormality in Korea. A 80-yr-old male was diagnosed with refractory anemia with excess blasts-2 (RAEB-2). Bone marrow aspiration smear showed 16% of blasts, which were large sized myeloid blasts with irregular margins and cytoplasmic vacuolation. Cytogenetic analysis of bone marrow cells revealed numercal and structural cytogenetic abnormalities including near-tetraploidy in 8 of 20 metaphases: 45,XY,add(1)(p36.1),del(10)(p11.2),del(11)(q13),-12,-16,der(17)t(11;17) (q13;q21),add(20)(q13.1),+mar[8]/85~90,idemx2[cp8]/46,XY[4]. After chemotherapy with decitabine, he showed pancytopenia during follow-up period and died of sepsis 14 months after the diagnosis.

Near-tetraploidy Acute Myeloid Leukemia with RUNX1-RUNX1T1 Rearrangement Due to Cryptic t(8;21) / 대한진단검사의학회지

Tetraploidy or near-tetraploidy is a rare cytogenetic abnormality found in AML, and is divided into primary and secondary forms. The secondary tetraploidy or near-tetraploidy found in AML is known to be specifically associated with t(8;21). In this case report, FISH analysis detected RUNX1-RUNX1T1 gene rearrangement in the absence of cytogenetic abnormality of t(8;21), which suggests the presence of unvailed t(8;21). This is the first case report of tetraploidy or near-tetraploidy AML with cryptic RUNX1/RUNX1T1 in Korea. Although the prognosis of tetraploidy or near- tetraploidy with t(8;21) is known to be poor, this patient shows a relatively good clinical course compared to other reported cases.