Aberrant myelomonocytic CD56 expression in Down syndrome is frequent and not associated with leukemogenesis

The impact of Down syndrome‐specific non‐malignant hematopoietic regeneration in the bone marrow on the detection of leukemic measurable residual disease

“…Further analyses of CD34 + myeloid progenitors from 20 non-DS AML or 20 ML-DS regenerating bone marrow specimens confirmed that those cells have statistically decreased expression of HLA-DR and increased expression of CD56, and statistically decreased percentage of HLA-DR + cells and increased percentage of CD56 + cells (Figure 2 and Supplemental Table 2, p < 0.01). For all the bone marrow specimens with CD56 + regenerative myeloblasts, expression of CD56 was detected on both monocytes and granulocytes, similar to previously described (Gadgeel et al, 2021;Karandikar et al, 2001;Langebrake et al, 2006). Notably, this DS-specific myeloid progenitor population, initially detected in bone marrow regenerating after AML chemotherapy, is also observed in regenerating bone marrows of DS patients after treatment for B-ALL (Figure 1).…”

“…Loss of HLA‐DR expression on progenitor cells is often one of the indicators of hematopoietic malignancy (Newman & Greaves, 1982). Previous studies have focused on the aberrant CD56 expression on granulocytes and monocytes in DS patients with TAM, AML, and ALL, but not particularly on CD34 + progenitor cells (Gadgeel et al, 2021; Karandikar et al, 2001).…”

“…It is noted that CD56 is not typically used for monitoring B‐ALL, but was utilized herein to show that this unique DS regeneration is independent of leukemia lineage and chemotherapy backbone (Karandikar et al, 2001; Langebrake et al, 2005; Wilson et al, 2016). Both Langebrake and Gadgeel et al proposed that RUNX1 and trisomy 21 are the major contributors for the aberrant CD56 expression and they suggested that RUNX1 and NCAM overexpression in hematopoiesis interplays with GATA1 somatic mutations (Gadgeel et al, 2021; Langebrake et al, 2006). The genetic regulation of those DS associated populations is currently under investigation.…”

“…This is due in part to the difficulty of obtaining normal bone marrows from these patients, and the low incidence of ML‐DS (approximately 150 patients in the US/year as about 10% of 6000 DS infants present with transient abnormal myelopoiesis [TAM] and 25% of those patients develop ML‐DS within 1–3 years and plus de novo cases each year) (Choi, 2008; Hasle, 2001; Mai et al, 2019; Zipursky et al, 1997). To date, several reports have indicated that bone marrow regeneration after a course of chemotherapy has unique features in patients with DS, focusing on CD56 on granulocyte and monocytes (Gadgeel et al, 2021; Karandikar et al, 2001; Langebrake et al, 2005; Wang et al, 2015). However, there has been no investigation of the frequency of CD56 positivity on the myeloid progenitor cells in regenerating bone marrow of DS patients, or any indication of what these findings could mean for flow based MRD assays.…”

Modeling Down Syndrome Myeloid Leukemia by Sequential Introduction of GATA1 and STAG2 Mutations in Induced Pluripotent Stem Cells with Trisomy 21

“…These results indicate that the megakaryocyte maturation was hindered in GATA1 and GATA1 STAG2 mutant cells, while STAG2 knockout alone did not have a significant effect. CD56, a marker with aberrant expression on TMD as well as DS-ML blasts [31,32], was expressed only in the megakaryoblasts expanded from iPSC lines with GATA1 mutation, but not with STAG2 knockout (Figure 3B). Furthermore, there was a statistically significant increase in CD56-expressing cells in the double-mutant line T21-1GS (43.8%, mean fluorescent intensity, MFI = 116,160 ± 2842) compared to T21-G1 (12.8%, p = 0.002; MFI = 21,262 ± 9077, p < 0.0001; Figure S3A,B).…”