CD44: expanding the toolKIT

Expanding the universe of mast cell diseases beyond tyrosine kinase inhibitors, in this issue of Blood, Mueller et al find that the invasion receptor CD44 is both a biomarker of and potential therapeutic target for mast cell neoplasms.¹ 

Patients with advanced systemic mastocytosis, a heterogeneous group including those with mast cell leukemia, associated hematologic neoplasms, or organ dysfunction related to mast cell infiltration, have the most aggressive disease and least favorable prognosis. Median survival for these unfortunate patients ranges from 6 to 36 months, on par with the most challenging myeloid malignancies. No approved therapies existed until April 2017, when the multikinase inhibitor midostaurin was approved based on an open-label study demonstrating a 60% overall response rate.²  Midostaurin, known best for targeting FLT3 in acute myeloid leukemia, also has recognized inhibitory activity against activated KIT. Alterations in KIT, most often the point mutation KITD816V, are canonical drivers of mast cell neoplasms, and more potent investigational inhibitors of KIT promise even deeper responses.³  These advances have highlighted the relevance of KIT in the initiation of mast cell disease. We’ve also learned that advanced disease is associated with multiple additional and familiar mutations in genes such as TET2, SRSF2, ASXL1, CBL, and RUNX1 that likely contribute to disease phenotype, progression, and treatment resistance.⁴ 

2018 is the year of the Mueller investigation. Eschewing geopolitics, Mueller et al focus instead on CD44, a stem cell marker/adhesion molecule known to be involved in homing to the niche and maintaining quiescence. Their study argues that CD44 is also relevant to the accumulation and survival of clonal mast cells in tissues. Using mast cell lines and primary patient samples, they find that CD44 is universally expressed on both normal and malignant mast cells, but with higher levels evident in clonal disease, and with expression levels increasing with disease severity. This gradient becomes more specific within progenitor populations, with CD44 expressed in advanced SM progenitors, but not in those from indolent disease and normal controls. Similarly, soluble CD44 is measurable in serum from patients with mast cell neoplasms, and levels are higher in patients with advanced systemic mastocytosis. In serial samples from a cohort of treated patients, soluble CD44 tracks with clinical response. In addition, higher levels of soluble CD44 negatively correlates with overall survival in advanced systemic mastocytosis.

Mechanistically, Mueller et al find that, unlike inhibitors of KIT, inhibitors of the Ras-MEK pathway and STAT5 inhibitors lead to downregulation of surface CD44 expression. And, to address CD44 more directly as a relevant therapeutic target, they find that RNA isolation-mediated knockdown of CD44 reduces tumor formation in a xenograft model. Taken together, CD44 appears to be both an invasion receptor in and biomarker of advanced systemic mastocytosis, and its regulation by RAS and STAT5 points at several potential therapeutic targets or combinatorial approaches.