MYC Rearrangements in Myeloid Neoplasms

Background:

8q24 /MYC rearrangements are an important mechanism of MYC protein dysregulation and most frequently occur in lymphoid neoplasms. Induced MYC expression in murine bone marrowrapidly induces leukemia and preferentially stimulates myeloid leukemogenesis in the absence of anti-apoptotic mutations (Luo et al, Blood, 2006). However, clinical data on patients with myeloid neoplasms and MYC rearrangement is very limited.

Methods:

We searched out databases for all cases with 8q24/ MYC rearrangements in the past 11 years and identified eight cases of myeloid neoplasms with MYC rearrangements which were confirmed by FISH analysis with MYC break apart rearrangement probe. The clinical and laboratory data, response to treatment and patient outcome were obtained through medical records. All samples were collected following institutional guidelines with informed consent in accordance with the Declaration of Helsinki.

Results:

Patients' clinical, pathological, and cytogenetic features are summarized in Table 1. There were 5 males and 3 females, with a median age of 60 years. Three patients were diagnosed with acute myeloid leukemia (AML), 1 with myelodysplastic syndrome (MDS) with excess blasts-2, and 4 with blastic plasmacytoid dendritic cell neoplasm (BPDCN).

Flow cytometry immunophenotyping was performed in all 8 patients. Of the 3 patients with AML, case #1 had aberrant expression of CD2 and cCD3, cases #2-3 had an aberrant expression of CD7. Case #4 had a myeloid phenotype. The immunophenotype of cases #5-8 were consistent with BPDCN with expression of CD2, CD4, and bright 123. MYC immunohistochemistry stain was performed in 5 patients, the percentage of cells with MYC expression was variable, but largely correlated with the percentage of blasts in the bone marrow.

Case #1 showed a normal diploid karyotype, but FISH revealed a cryptic der(14)ins(8;14)(q24;q32q32); Cases #4 and #8 had t(8;14)(q24;q32) as the sole chromosomal abnormality; the other 5 cases had a complex karyotype. The partner chromosomes for 8q24 were 14q32 (cases # 1, 4 and 8), 6p21 (case #5), Xq24 (case #6), 3p25 (case #7), and unknown in cases #2 and #3. FISH showed MYC rearrangement in a median of 80% cells (ranges, 4.5% -97%).

The treatments were summarized in Table 1. Three AML patients did not response to chemotherapies or had a quick relapse after a short remission, all 3 patients died within 1 year. Case #4 (MDS) developed AML at 1 month and died at 2.2 months after the diagnosis of MDS. Of the four BPDCN patients, case #4 had an early death due to infection, the other 3 patients responded well to ALL-based regimens (Hyper-CVAD, n=2; COG ALL L0434, n=1), two were alive and in complete remission, one had been in remission but died of pulmonary hemorrhage at 26 months.

Conclusions:

8q24/ MYC rearrangement occurs rarely in myeloid neoplasms, often with partner genes other than the ones encoding immunoglobulin. Patients with AML/MDS were often resistant to chemotherapies, while patients with BPDCN responded well to ALL-based regimens.

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