Chronic myeloid leukemia (CML) is caused by the BCR-ABL1 tyrosine kinase, the product of the Philadelphia chromosome. In the chronic phase of CML (CP-CML), myeloid cells expand, but maintain differentiation. BCR-ABL1 tyrosine kinase inhibitors (TKIs) frequently induce deep responses, but do not eliminate primitive, quiescent CML stem cells (LSCs), whose survival is independent of BCR-ABL1 kinase activity.

As a result, most patients require lifelong TKI therapy to prevent recurrence of active CML. In ~10% of patients, a block of differentiation converts CP-CML to blast phase CML (BP-CML), an acute leukemia of typically myeloid phenotype. Blasts from many BP-CML cases have acquired BCR-ABL1 independence and are resistant to TKIs.

Our preliminary data show that MS4A3 knockdown inhibits differentiation, enhances TKI resistance and promotes survival of CML stem and progenitor cells (LSPCs) in vitro and in vivo. By contrast, ectopic MS4A3 expression increases differentiation and TKI sensitivity. Consistent with these data, low MS4A3 expression correlates with shorter survival in CP-CML. At a mechanistic level, MS4A3 enhances IL-3 and GM-CSF signaling in CML CD34+ cells by promoting endocytosis of β common chain (βc) cytokine receptors, suggesting that MS4A3 is not merely a marker, but a positive regulator of myeloid differentiation.

In support of this, delivery of MS4A3-containing nanoparticles to BP-CML CD34+ cells induce differentiation and reduces colony formation. These data suggest that MS4A3 promotes differentiation by enhancing βc receptor endocytosis and IL-3/GM-CSF signaling. TKI resistant LSPCs reduce MS4A3 to blunt response to differentiation-inducing cytokines to maintain an undifferentiated, therapy-resistant state, possibly coopting a physiological stress response mechanism.