According to a study published in Blood Advances, researchers identified the tumor suppressor gene CADM1 as a major candidate gene in myelodysplastic syndromes (MDS) with del(11q). In addition to CADM1, ATM, CBL, and KMT2A were also deleted or mutated in cases of MDS and myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) with del(11q).
“The deletion of the long arm of chromosome 11, del(11q), is a rare but recurrent clonal event in MDS,” the researchers wrote in their report.
The retrospective study represents the largest series of cases of MDS and MDS/MPN with del(11q) to date, including 113 patients (103 with MDS and 10 with MDS/MPN). The researchers evaluated clinical, cytological, cytogenetic, and molecular features of the disease and compared them with those of a control cohort of 88 patients with MDS without del(11q).
Among the 113 patients (median age, 74 years; range, 31-94), there was a female predominance (sex ratio, 0.74). Compared with the control group, the del(11q) group had a similar overall survival (P = .84), lower monocyte count (median, 0.2 × 109/L vs 0.4 × 109/L; P = .0004), and increased dysmegakaryopoiesis (78-80% vs 57%; P = .001).
The del(11q) appeared as an interstitial deletion in 90% of cases (102/113). In 11 cases, it was more complex as an unbalanced translocation, a di- or tri-centric chromosome 11, or a ring chromosome). In most cases, the del(11q) encompassed the 11q22-23 region containing the ATM, KMT2A, and CBL genes, and the common deleted region (11q23.2) was centered on an intergenic region between CADM1 and NXPE2.
To further examine the impact of the common deleted region, the researchers evaluated gene expression of CADM1 and NXPE2 in 21 MDS, 10 chronic myelomonocytic leukemia, and 55 AML samples. They found that CADM1 was expressed in all myeloid cells analyzed while NXPE2 was not. CADM1 had 71-fold higher expression (mean expression relative to ABL1, 5.9%; range, 0.08-138%) than NXPE2 (0.08%; range, 0-0.75%).
The researchers then demonstrated that Cadm1 deletion in murine hematopoietic progenitor (Lineage–Sca1+Kit+) cells modifies the lymphoid-to-myeloid ratio in bone marrow of transplanted mice. The perturbation persisted at 8 months after transplantation, but recipients did not develop hematopoietic neoplasms, even after a period of 21 months, suggesting clonal transformation in mice requires collaborative oncogenic events.
“[W]e show that CADM1 may be important in the physiopathology of the del(11q) MDS, extending its role as tumor-suppressor gene from solid tumors to hematopoietic malignancies,” concluded the authors.
Lafage-Pochitaloff M, Gerby B, Baccini V, et al. The CADM1 tumor suppressor gene is a major candidate gene in MDS with deletion of the long arm of chromosome 11. Blood Adv. 2022;6(2):386-398. doi:10.1182/bloodadvances.2021005311