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Hum Mutat. 2018 Apr;39(4):579-587. doi: 10.1002/humu.23399. Epub 2018 Jan 19.

Somatic mutations activating Wiskott-Aldrich syndrome protein concomitant with RAS pathway mutations in juvenile myelomonocytic leukemia patients.

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Department of Molecular Medicine, University of Padova, Padova, Italy.
Department of Biomedical Sciences, University of Padova, Padova, Italy.
Laboratory of Onco-Hematology, Department of Women's and Children's Health, University of Padova, Padova, Italy.
Pediatric Hematology Oncology, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
Oncologia ed Ematologia Pediatrica "Lalla Seràgnoli", University of Bologna, Bologna, Italy.
Department of Pediatric Onco-Hematology, IRCCS Ospedale Pediatrico Bambino Gesù, Roma, Italy.


The WAS gene product is expressed exclusively in the cytoplasm of hematopoietic cells and constitutional genetic abrogation of WASP leads to Wiskott-Aldrich syndrome (WAS). Moreover, mutational activation of WASP has been associated with X-linked neutropenia. Although studies reported that patients with constitutional WAS mutations affecting functional WASP expression may present juvenile myelomonocytic leukemia (JMML)-like features, confounding differential diagnosis above all in the copresence of mutated RAS, an activating somatic mutation of WASP has not been previously described in JMML patients. In our ongoing studies on JMML genomics, we at first detected a somatic WAS mutation in a major clone found at two consecutive relapses in one of two twins with JMML. Both twins were treated with hematopoietic stem cell transplantation after diagnosis of JMML. The somatic WAS mutation detected here displayed an activating WASP phenotype. Screening of 46 sporadic JMML patients at disease onset for mutations in the same PBD domain of WAS revealed two additional singleton patients carrying minor mutated clones. This is the first study to associate somatically acquired WASP mutations with a hematopoietic malignancy and increases insight in the complexity of the genomic landscape of JMML that shows low recurrent mutations concomitant with general hyperactivation of RAS pathway signaling.


JMML; RAS pathway; WASP; sequencing


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