Session: 631. Myeloproliferative Syndromes and Chronic Myeloid Leukemia: Basic and Translational: Poster III
Hematology Disease Topics & Pathways:
Research, Fundamental Science, Translational Research, Diseases, Myeloid Malignancies
We performed additional studies to further define the genetic events responsible for HMGA1 and HMGA2 overexpression (OE) in MF. HMGA2OE in MPNs has been previously attributed to balanced translocations involving chromosome 12 at breakpoints 12q13-15 (Marquis et al. Blood Cancer J 2018). We have identified novel genomic deletions at 12q14.3 (named Δ3’HMGA2) in 9% of our cohort of 169 MF patients, which were not found in PV, ET, MDS/MPN or MPN-U patients. Such deletions result in loss of most of the 3’UTR in HMGA2 exon 5 that includes MIRLET7 binding sites leading to HMGA2OE. By performing scRNA-seq, we were able to identify the cells harboring Δ3’HMGA2 in MNCs from MF patients with such deletions but not from patients with normal HMGA2. Structural abnormalities involving HMGA1 at 6p21.31 were not observed. The relative levels of HMGA2 transcripts were significantly higher in MNCs of MF patients with HMGA2 aberration (Δ3’HMGA2 or HMGA2 rearrangement but not Δ3’HMGA2) than those lacking such changes (2.3-fold, p=0.008).
While HMGA2 expression level was not influenced by the MPN driver mutation (p=0.5), HMGA2 abnormalities occurred more frequently in patients with non-JAK2 driver mutations (63%), predominantly CALR (58%), which contrasts with their general distribution (57% JAK2 and 28% CALR). In fact, 23% (11/48) of all CALR+ MF patients carried HMGA2 aberrations.
ASXL1 mutations frequently co-occurred in MF patients with an HMGA2 aberration (84%; none had EZH2 mutations) as compared to only 28% (42/150) in patients lacking an HMGA2 abnormality (p≤0.001). We found no difference in HMGA2 levels in MF patients lacking an HMGA2 aberration based on the presence or absence of ASXL1 mutation/deletion (p=0.95). However, HMGA2 levels were significantly higher in MF patients with co-occurring HMGA2 and ASXL1 aberrations as compared to the prior two groups (3.3-fold, p=0.0002; 4.1-fold, p=0.00001). Furthermore, 42% (8/19) patients with HMGA2 abnormalities developed >5% peripheral blood blasts and 5 (26.3%) progressed to MPN-accelerated phase/blast phase (AP/BP) during their clinical course. Of these, four patients developed MPN-AP/BP within 3 years of detection of Δ3’HMGA2. Conversely, only 7.1% (3/42) MF patients who lacked Δ3’HMGA2 progressed.
We conclude that HMGA1 and HMGA2 each play a role in MF progression, with structural abnormalities involving MIRLET7 binding sites of HMGA2 occurring more frequently in MF patients with CALR mutations. These abnormalities result in HMGA2OE independent of concurrent mutations in ASXL1 or EZH2, and their frequency differs depending on the type of MPN driver mutation. Mining scRNA-seq data from patients with and without Δ3’HMGA2 will enable us to identify possible lineage skewing, differentially expressed genes and regulatory networks driven by HMGA2OE that control MF progression.
Disclosures: Schaniel: Cellenkos Inc: Research Funding; Sumitomo Pharma: Research Funding; Dexoligo Therapeutics by Dexcel Pharma Technologies Ltd.: Research Funding. Tremblay: Sobi: Consultancy, Research Funding; Sumitomo: Research Funding; Cogent Biosciences: Consultancy, Research Funding; Gilead: Research Funding; Novartis: Consultancy; Abbvie: Consultancy; Pharmaessentia: Consultancy; Sierra Oncology: Consultancy; GSK: Consultancy. Marcellino: Cellarity: Consultancy. Hoffman: Kymera: Research Funding; Protagonist Therapeutics: Consultancy; Karyopharm therapetics: Research Funding; Cellenkos: Research Funding; Dexcel: Research Funding; Silence Therapeutics: Consultancy.
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