Circulating nucleosomes in hematological malignancy.

Abstract

e20078 Background: There are over 700,000 new cases of non-Hodgkin lymphoma (NHL), acute myeloid leukaemia (AML) and acute lymphocytic leukaemia (ALL) diagnosed globally each year and approximately 415,000 deaths. The non-specific symptoms of lymphoma and leukemia often delay diagnosis. We investigated the circulating levels of intact nucleosomes containing the histone H3.1 isoform (Nu.Q-H3.1) in a variety of solid tumors, NHL, AML, ALL, and in healthy subjects. Methods: We measured levels of Nu.Q-H3.1 in plasma samples taken from 62 healthy volunteers (mean age = 45 yrs) and 329 patients diagnosed with cancer (mean age = 56 yrs), including 25 patients diagnosed with each of cancer of the bladder, bone, brain, oesophagus, cervix, skin, head & neck or melanoma, 21 patients diagnosed with uterine cancer as well as with NHL (n = 25), AML (n = 25) and ALL (n = 8). The cohort included samples taken from patients at diagnosis and at relapse. Whole blood samples were collected in EDTA plasma tubes, double-centrifuged at 1500 rcf for 15 minutes within 2 hrs of blood draw, after which plasma was transferred to a cryotube and frozen immediately until analysis. Plasma samples (20µl) were analyzed in duplicate for Nu.Q-H3.1 using an ELISA method developed and validated to CLSI guidelines. Results: We observed elevated levels of Nu.Q-H3.1 in the patients diagnosed with various cancers. Only 14 of 271 patients with a solid tumor had levels > 200ng/ml. In contrast the median Nu.Q-H3.1 levels observed for NHL, AML and ALL were 276, 284 and 585ng/ml respectively. The median nucleosome level in 62 healthy subjects was 40ng/ml; the highest level was 198ng/ml. The AUC for all patients diagnosed with NHL, AML or ALL (n = 54) vs healthy volunteers was 91% with a sensitivity of 74% at 95% specificity. The AUC for the subset of patients newly diagnosed with NHL, AML or ALL (n = 31) vs healthy volunteers was 92% with a sensitivity of 81% at 95% specificity. Conclusions: Elevated nucleosome levels have been reported for a number of diseases. Our early results indicate that levels of Nu.Q-H3.1 are particularly elevated in haematological malignancies and may be a useful diagnostic tool warranting further study.

Circulating Histones to Detect and Monitor the Progression of Cancer

“…Several studies have shown drastically increased circulating histones and histone complexes in patients with hematologic malignancies [ 115 , 116 , 118 , 119 , 120 ] ( Table 3 ). Similarly, high levels of nucleosomes containing the histone H3.1 isoform (Nu.Q-H3.1) were found in non-Hodgkin lymphoma (NHL), acute myeloid leukemia (AML), and especially in acute lymphocytic leukemia (ALL), with a median of 276 ng/mL, 284 ng/mL and 585 ng/mL, respectively, as compared to 40 ng/mL for healthy individuals [ 119 ]. Furthermore, Mueller et al indicated that circulating histone complexes could act as a predictive marker of chemotherapy response in acute myeloid leukemia patients [ 121 ].…”