Megakaryocytes harbour the del(5q) abnormality despite complete clinical and cytogenetic remission induced by lenalidomide treatment

Br J Haematol. 2018 Feb;180(4):526-533. doi: 10.1111/bjh.15094. Epub 2018 Jan 29.


The mechanisms underlying lenalidomide-resistance of del(5q) MDS stem cells remain to be elucidated and may include cell-intrinsic as well as microenvironmental causes. Abnormal hypolobated megakaryocytes constitute one of the hallmarks of del(5q) MDS. We hypothesized that these cells have potential implications for the regulation of haematopoietic stem cells (HSC) similarly to what has recently been described for megakaryocytes in the murine system. Therefore, we conducted a study to determine the response of abnormal hypolobated megakaryocytes to lenalidomide therapy. We studied lenalidomide-treated patients in the MDS-004 trial as well as a cohort seen at our institution. Morphological evaluation at time of complete cytogenetic remission (CCyR) demonstrated the persistence of hypolobated megakaryocytes in all evaluable patients (n = 9). Furthermore, we provide evidence that the abnormal hypolobated morphology is restricted to del(5q) megakaryocytes, both at diagnosis and during CCyR. Using fluorescence in situ hybridisation analysis on flow-sorted stem- and progenitor populations, we observed a similar degree of clonal involvement in megakaryocyte-erythroid-progenitors as in HSC. Taken together, our findings suggest that megakaryocyte morphology might aid in the evaluation of patients where discontinuation of lenalidomide is considered and offers interesting hypotheses for further investigation of lenalidomide resistance.

Keywords: fluorescence in-situ hybridization; megakaryocytes; myelodysplastic syndrome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / therapeutic use*
  • Bone Marrow / pathology
  • Chromosome Deletion*
  • Chromosomes, Human, Pair 5*
  • Clonal Evolution
  • Cytogenetic Analysis
  • Hematologic Neoplasms / diagnosis
  • Hematologic Neoplasms / drug therapy*
  • Hematologic Neoplasms / genetics*
  • Humans
  • Immunophenotyping
  • In Situ Hybridization, Fluorescence
  • Lenalidomide
  • Megakaryocyte-Erythroid Progenitor Cells / metabolism
  • Megakaryocyte-Erythroid Progenitor Cells / pathology
  • Megakaryocytes / metabolism*
  • Megakaryocytes / pathology
  • Remission Induction
  • Thalidomide / administration & dosage
  • Thalidomide / adverse effects
  • Thalidomide / analogs & derivatives*
  • Thalidomide / therapeutic use
  • Treatment Outcome


  • Antineoplastic Agents
  • Thalidomide
  • Lenalidomide