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A therapeutic strategy for treating cancer is to target and eradicate cancer stem cells (CSCs) without harming their normal stem cell counterparts. The success of this approach relies on identification of molecular pathways that selectively regulate CSC function. Using BCR-ABL-induced chronic myeloid leukemia (CML) as a disease model for CSCs, we show that BCR-ABL down-regulates the B lymphoid kinase ( Blk ) gene through c-Myc in leukemia stem cells (LSCs) in CML mice and that Blk functions as a tumor suppressor in LSCs but does not affect normal hematopoietic stem cells (HSCs) or hematopoiesis. Blk suppresses LSC function through a pathway involving an upstream regulator, Pax5, and a downstream effector, p27. Inhibition of this Blk pathway accelerates CML development, whereas increased activity of the Blk pathway delays CML development. Blk also suppresses human CML stem cells. Our results demonstrate the feasibility of selectively targeting LSCs, an approach that should be applicable to other cancers.

Some patients with systemic mastocytosis have concurrent hematological neoplasms, designated in the World health Organization (WHO) classification as systemic mastocytosis with associated clonal hematological non-mast-cell lineage disease (SM-AHNMD). In this study, we analyzed 29 patients with SM-AHNMD and compared them to 40 patients with pure SM. The AHNMDs were classified as chronic myelomonocytic leukemia (CMML)(n=10), myelodysplastic syndrome (MDS)(n=7), myeloproliferative neoplasms (n=4), B-cell lymphoma/leukemia/plasma cell neoplasms (n=7) and acute myeloid leukemia (n=1). Patients with SM-AHNMD were older, more frequently had constitutional symptoms and hematological abnormalities, less often had skin lesions, and had an inferior overall survival compared with pure SM patients (48 months versus not-reached, p<0.001). Karyotypic abnormalities were detected in 9/28 (32%) patients with SM-AHNMD but not in pure SM patients (p<0.001). Combined imaging/ fluorescence-in-situ hybridization performed in 4 SM-AHNMD cases revealed shared abnormal signals in mast cells and myeloid cells in 2 patients with SM-CMML and 1 patient with SM-MDS, but not in the mast cells of a case SM-associated with chronic lymphocytic leukemia with ATM-deletion. Quantitative mutation analysis showed higher levels of mutant KIT D816V in SM-CMML and SM-MDS than in pure SM (p<0.001). Our data indicate that the SM-AHNMD category in the WHO classification is heterogeneous, including clonally related and unrelated forms of AHNMD. The presentation, treatment and outcome of patients with SM-AHNMD is often dictated by the type of AHNMD.

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