Grants Awarded

Principal Investigator:
Astrid van Halteren
Erasmus University Medical Center Rotterdam,
Rotterdam, Netherlands

Date of Award:
December 2024

Amount of Award:
$50,000

Layperson Summary:

The histiocytoses are rare disorders confined to the hematopoietic system, an organ system responsible for the daily production of various types of white and red blood cells. These diseases cause inflammation and tissue destruction in one or more organ systems. Pathological cells present in histiocytosis biopsies often display cancer-associated mutations in their genome. Yet, a considerable proportion of biopsies – particularly those associated with xanthogranuloma or Rosai Dorfman Destombes disease

– are devoid of such mutations. We want to investigate whether macrophage-like histiocytes in the latter biopsies have developed from an alternative precursor cell. To this end, we propose to perform extensive molecular analysis on a total of 50 xanthogranuloma biopsies stored in the archives of Dutch pathology centers linked to the Dutch Nationwide Pathology Databank. To increase our chance to find relevant genomic sequences that reveal the cell-of­ origin wherefrom pathological histiocytes are generated, we propose to analyze additional biopsies of the 25 patients in this cohort who presented with an additional hematological malignancy. We hypothesize that the biopsies from xanthogranuloma patients with an additional myeloid cancer will display typical cancer-associated mutation including N/KRAS mutations. On the contrary, biopsies from xanthogranuloma patients with an additional lymphoid cancer will display DNA sequences reminiscent of B-cell origin. In addition, we want to set up an in vitro culture system wherein human blood cells can be generated from so called induced pluripotent stem cells. Using this model, we will test the feasibility to generate macrophages – the hallmark cells of xanthogranulomatous lesions – from in vitro generated monocytes or B-lymphoid cells.