Background: Recent genome-wide microarray-based research investigations have revealed a high frequency of submicroscopic copy number alterations (CNAs) in the myelodysplastic syndromes (MDS), suggesting microarray-based comparative genomic hybridization (aCGH) has the potential to detect new clinically relevant genomic markers in a diagnostic laboratory. Results: We performed an exploratory study on 30 cases of MDS, myeloproliferative neoplasia (MPN) or evolving acute myeloid leukemia (AML) (% bone marrow blasts ≤ 30%, range 0-30%, median, 8%) by aCGH, using a genome-wide bacterial artificial chromosome (BAC) microarray. The sample data were compared to corresponding cytogenetics, fluorescence in situ hybridization (FISH), and clinical-pathological findings. Previously unidentified imbalances, in particular those considered submicroscopic aberrations (< 10 Mb), were confirmed by FISH analysis. CNAs identified by aCGH were concordant with the cytogenetic/FISH results in 25/30 (83%) of the samples tested. aCGH revealed new CNAs in 14/30 (47%) patients, including 28 submicroscopic or hidden aberrations verified by FISH studies. Cryptic 344-kb RUNX1 deletions were found in three patients at time of AML transformation. Other hidden CNAs involved 3q26.2/EVI1, 5q22/APC, 5q32/TCERG1,12p13.1/EMP1, 12q21.3/KITLG, and 17q11.2/NF1. Gains of CCND2/12p13.32 were detected in two patients. aCGH failed to detect a balanced translocation (n = 1) and low-level clonality (n = 4) in five karyotypically aberrant samples, revealing clinically important assay limitations. Conclusions: The detection of previously known and unknown genomic alterations suggests that aCGH has considerable promise for identification of both recurring microscopic and submicroscopic genomic imbalances that contribute to myeloid disease pathogenesis and progression. These findings suggest that development of higher-resolution microarray platforms could improve karyotyping in clinical practice.

Background: Chronic lymphocytic leukemia (CLL) is a highly variable disease with life expectancies ranging from months to decades. Cytogenetic findings play an integral role in defining the prognostic significance and treatment for individual patients.Results: We have evaluated 25 clinical cases from a tertiary cancer center that have an established diagnosis of CLL and for which there was prior cytogenetic and/or fluorescencein situhybridization (FISH) data. We performed microarray-based comparative genomic hybridization (aCGH) using a bacterial artificial chromosome (BAC)-based microarray designed for the detection of known constitutional genetic syndromes. In 15 of the 25 cases, aCGH detected all copy number imbalances identified by prior cytogenetic and/or FISH studies. For the majority of those not detected, the aberrations were present at low levels of mosaicism. Furthermore, for 15 of the 25 cases, additional abnormalities were detected. Four of those cases had deletions that mapped to intervals implicated in inherited predisposition to CLL. For most cases, aCGH was able to detect abnormalities present in as few as 10% of cells. Although changes in ploidy are not easily discernable by aCGH, results for two cases illustrate the detection of additional copy gains and losses present within a mosaic tetraploid cell population.Conclusions: Our results illustrate the successful evaluation of CLL using a microarray optimized for the interrogation of inherited disorders and the identification of alterations with possible relevance to CLL susceptibility.

Gene fusions involving NUTM1 have been increasingly recognized in hematologic malignancies, though their role in acute myeloid leukemia (AML) remains poorly understood. We retrospectively analyzed 565 unique AML patients with reported fusion results who underwent comprehensive next-generation sequencing (NGS) between March 2022 and December 2023. Among them, three novel in-frame NUTM1 fusion transcripts, LARP1::NUTM1, ARHGAP15::NUTM1, and GABPB1::NUTM1, were identified in three relapsed or refractory AML cases, all with monocytic differentiation. Ancillary studies included flow cytometry, cytogenetics, FISH, and comprehensive mutational profiling. All three patients eventually relapsed and succumbed to their disease, despite initial responses in one case. Each case also harbored co-occurring mutations associated with adverse prognosis, such as BCOR, ASXL1, and RUNX1. These findings suggest NUTM1 fusions in AML could represent a distinct molecular subset with potentially poor prognosis, warranting further functional and clinical investigation to clarify their biological and therapeutic significance.