SNP-A Karyotyping Demonstrates a High Incidence of Segmental Uniparental Disomy in Patients with CMML and Shows Impact of Newly Identified Chromosomal Aberrations on Clinical Course.
Authors: Dunbar Andrew J. , Gondek Lukasz P. , Tiu Ramon V. , Karp Judith E. , Wang Xiao Fei P. , Levis Mark J. , McDevitt Michael A. , Maciejewski Jaroslaw P. 
Published: April 2020

Abstract
The WHO classification recognizes chronic myelomonocytic leukemia (CMML) as an overlap syndrome sharing clinical and histomorphologic features with both MDS and MPD. Unlike in CML or classical MPD, which are often characterized by recurrent translocations or activating mutations, only 1/3 of CMML patients harbor lesions (e.g. balanced translocations that include PDGFb as a fusion partner). Also frequent are unbalanced aberrations similar to those seen in classical MDS. Of note is that IPSS assigns prognosis only to a portion of patients with CMML (those with &gt;10% of blasts and/or high WBC counts). Since chromosomal defects have a major impact on the diagnosis and prognosis of myeloid malignancies, it is likely that cytogenetic methods with higher resolution and an ability to detect uniparental disomy (UPD) could explain clinical heterogeneity and point to potential therapeutic targets in CMML. We applied 250K SNP-arrays (SNP-A) to examine karyotype and identify previously cryptic defects in patients with low grade and advanced forms of CMML. SNP-A allows for detection of clones spanning 25–50% of total cell population, and fidelity of LOH calls is &gt;99% as shown by analysis of chromosome (chr.) X in males. Any deletions, duplications, and/or UPD found by SNP-A in 76 controls or those on internet databases were considered copy number variants (CNV) and excluded from analysis. In total, we studied 77 patients with CMML; 42/77 showed abnormal MC, including most often lesions commonly associated with MDS/CMML, such as +8 (N=5) and +19 (N=2). DNA was available for SNP-A karyotyping in 46 patients. Abnormal karyotype was detected in 19/46 patients (40%) by MC compared to 37/46 patients (79%) by SNP-A. Examples of newly detected lesions included microdeletions of chrs. 12 and 7, and various micro-duplications/deletions. Remarkably, we found (perhaps in analogy to UPD9p seen in MPD) a high prevalence of segmental UPD, occurring in 20/47 patients (43%) with significant recurrence on chrs. 4 (N=4), 6 (N=4), and 11 (N=4). 7/20 patients had UPD as a sole or isolated abnormality. In 3 these patients, UPD11q was the sole contributing lesion while in one patient with UPD11, only one additional lesion, a small microdeletion of chr. 3, was found. Of note is that previously we have found also UPD11q in 4/29 patients with MDS/MPD-U. When we analyzed SNP-A results in CMML patients according to blast counts (CMML-1/2) and WBC (myeloproliferative type (MP) vs. myelodysplastic type (MD)), CMML-2 patients showed a higher frequency/more complex lesions, likely acquired in the process of transformation (1.5 vs. 2.2 avg. lesions). In addition to identifying abnormal overlapping/recurrent aberrations, SNP-A karyotyping has a potential clinical utility. When we stratified patients according to SNP-A detected lesions, we found a statistically significant difference between overall survival of patients with normal MC and normal SNP-A vs. those with normal MC but abnormal SNP-A (p=0.03, 40.2 vs. 7.3 months). In summary, SNP-A-based karyotyping complements MC and allows for precise definition of chr. aberrations in patients with CMML, including copy-neutral LOH. UPD is common in CMML and overlapping regions may point to potential causative genes.