Patients with high‐risk myelodysplastic syndrome can have polyclonal or clonal haemopoiesis in complete haematological remission

Abstract

Summary. The clonality of mature peripheral blood-derived myeloid and lymphoid cells and bone marrow haemopoietic progenitors from 18 females with myelodysplasia (MDS) (five refractory anaemia, RA; one RA with ringed sideroblasts, RARS; three chronic myelomonocytic leukaemia, CMML; four RA with excess of blasts, RAEB; five RAEB in transformation, RAEB-t) was studied by X-chromosome inactivation analysis. Using the human androgen-receptor (HUMARA) assay, we analysed the clonal patterns of highly purified immature CD34 þ 38 ¹ and committed CD34 þ 38 þ marrow-derived progenitors, and CD16 þ 14 ¹ granulocytes, CD14 þ monocytes, CD3 þ T and CD19 þ B lymphocytes from peripheral blood. In high-risk patients (RAEB, RAEB-t), clonality analysis was performed before and after intensive remission-induction treatment. All patients, except one with RA, had predominance of a single clone in their granulocytes and monocytes. The same clonal pattern was found in CD34 þ progenitor cells. In contrast, CD3 þ T lymphocytes were polyclonal or oligoclonal in 14/18 patients. Xchromosome inactivation patterns of CD19 þ B cells were highly concordant with CD3 þ T cells except for two patients (one RA, one CMML) with monoclonal B and polyclonal T lymphocytes, therefore suggesting a clonal mutation in a progenitor common to the myeloid and B-lymphoid lineages or the coexistence of MDS and a B-cell disorder in these particular patients. After high-dose non-myeloablative chemotherapy, polyclonal haemopoiesis was reinstalled in the mature myeloid cells and immature and committed marrow progenitors in three of four patients achieving complete haematological remission. Therefore we conclude that most haematological remissions in MDS are associated with restoration of polyclonal haemopoiesis.

Loss of T-lymphocyte clonal dominance in patients with myelodysplastic syndrome responsive to immunosuppression

“…In previous studies where T cells have been evaluated by studying the pattern of inactivation of X chromosomes in female patients, the majority of T lymphocytes were found to be polyclonal and therefore not derived from the clonal dysplastic hematopoietic precursors. 20,21 Moreover, the clonal T-cell expansions evaluated in this study appear to have undergone normal development. The sequences of the CDR3 regions from these clonal populations contained nucleotide changes consistent with the normal junctional diversity that occurs during thymic development.…”

CD34+ marrow progenitors from MDS patients with high levels of intramedullary apoptosis have reduced expression of α4β1 and α5β1 integrins

“…37,38 This is a drawback of many MDS studies when separation of clonal and nonclonal progenitors is not possible. Nevertheless, we believe that minor nonclonal fractions could only result in neglectable variations of the highly significant differences in a4b1 and a5b1 expression levels we observed in this study.…”

Circulating myeloid and lymphoid precursor dendritic cells are clonally involved in myelodysplastic syndromes

“…25 On the other hand, again consistent with the literature, normal FISH patterns were found in helper T cells (Table 2), cytotoxic T cells and B cells (not shown). [1][2][3][4][5][6]25 To the best of our knowledge, these are the first data reporting absolute pDC numbers in MDS-type refractory anemia of refractory anemia with ringed sideroblasts. With a highly reproducible single-platform procedure, we show that absolute and relative counts of circulating myeloid as well as lymphoid pDC in MDS patients are reduced about 50% compared with healthy volunteers.…”

“…[1][2][3][4][5][6] Yet, MDS, especially with trisomy 8 and/or HLA-DR15, can respond to T-cell targeting immunosuppression. [7][8][9][10][11][12] This paradoxical observation sparked renewed interest in T-cell mediated mechanisms comodelling the presentation of MDS, and, in particular, in T-cell interactions with antigen-presenting cells (APC).…”