P53 protein overexpression in de novo acute myeloid leukemia patients with normal diploid karyotype correlates with FLT3 internal tandem duplication and worse relapse-free survival.

Although ~50% of acute myeloid leukemia (AML) patients have a normal diploid karyotype by conventional cytogenetics at diagnosis, this patient subset has a variable disease course and outcome. Aberrant overexpression of the p53 protein is usually associated with TP53 alterations and a complex karyotype, but the prevalence and impact of p53 overexpression in AML with diploid cytogenetics is unknown. We examined 100 newly diagnosed AML patients to evaluate the impact of p53 expression status quantified in bone marrow core biopsy samples using immunohistochemistry and computer-assisted image analysis. A total of 24 patients had p53 overexpression defined as 3+ staining intensity in ≥5% of cells; this finding correlated with lower platelet counts (P = .002), absence of CD34 expression in blasts (P = .009), higher bone marrow blast counts (P = .04), and a higher frequency of FLT3 internal tandem duplication (P = .007). Overexpression of p53 independently predicted for shorter leukemia-free survival in patients who underwent allogeneic stem cell transplantation by univariate (P = .021) and multivariate analyses (P = .004). There was no correlation between MDM2 and p53 protein expression in this cohort. We conclude that p53 expression evaluated by immunohistochemistry in bone marrow biopsy specimens at the time of AML diagnosis may indicate distinct clinical characteristics in patients with normal diploid cytogenetics and is a potentially valuable tool that can enhance risk-stratification.

Chronic Myelomonocytic Leukemia With Fibrosis Is a Distinct Disease Subset With Myeloproliferative Features and Frequent JAK2 p.V617F Mutations.

A subset of patients with chronic myelomonocytic leukemia (CMML) presents with significance myelofibrosis. In myelodysplastic syndromes, significant myelofibrosis has been associated with adverse outcomes and p53 dysregulation. However, in CMML the clinical and molecular correlates of significant myelofibrosis at presentation remain poorly understood. From a cohort of 651 CMML patients, we identified retrospectively 20 (3.1%) cases with moderate to severe reticulin fibrosis (CMML-F) detected at diagnosis, and we compared them to CMML patients without fibrosis (n=631) seen during the same period. Patients with CMML-F had a median age of 69.8 years (range, 24.8 to 91.2 y) and most (13; 65%) were men. Patients with CMML-F differed significantly from other CMML patients across the following parameters: white blood count, absolute monocyte count, serum lactate dehydrogenase level, splenomegaly, and bone marrow blast percentage. Notably, the frequency of JAK2 p.V617F mutation was higher in CMML-F patients compared with other CMML patients (P<0.001). Most CMML-F patients (12/20; 60%) had myeloproliferative CMML. Dysregulation of p53 was uncommon in CMML-F. CMML-F patients tended to have a shorter median overall survival compared with other CMML patients (P=0.079). Multivariate analysis using the Cox proportional hazards model showed an independent association between CMML-F and overall survival (P=0.047). In summary, unlike typical CMML, CMML-F is commonly associated with JAK2 p.V617F. The high frequency of myeloproliferative features and JAK2 p.V617F mutation, and the low frequency of p53 dysregulation, suggest that fibrosis in the context of CMML has a different pathogenesis from that previously reported in myelodysplastic syndrome.