Malignant HematopoiesisLkb1 deletion in murine B lymphocytes promotes cell death and cancer

•Somatic LKB1 deletions are present in B-cell lymphomas.•Lkb1 expression exerts pro-survival effect in lymphocytes.•Lkb1 inactivation facilitates transformation of B cells but does not facilitate transformation of T cells.•In the absence of Lkb1, Kras activation rescues apoptosis and promotes leukemia development in T cells but not in B cells.

LKB1 (also known as STK11) is a potent tumor suppressor in solid tumors, such as melanoma and lung adenocarcinoma, but inactivation in hematopoietic cells causes cell death without signs of tumorigenesis. We noted somatic LKB1 deletion or mutation at low frequency in human B-cell lymphoma. To determine if LKB1 inactivation is a passenger or driver event in lymphoid cancers, we examined the effects of conditional inactivation of Lkb1 in murine lymphocytes. Consistent with prior reports, Lkb1 deletion in either T or B cells resulted in massive, lineage-specific apoptosis. Surprisingly, despite an 80% reduction of peripheral B-cell number, animals harboring somatic B-lineage Lkb1 deletion developed aggressive B-cell lymphoma with high penetrance and moderate latency. Malignant B cells exhibited somatic Lkb1 recombination. In contrast, Lkb1 deletion in T cells did not promote tumorigenesis. Concomitant Ras activation with Lkb1 deletion reduced T-cell apoptosis, but did not enhance tumor formation in T or B cells. These results suggest that although physiologic LKB1 expression exerts a potent pro-survival effect in lymphocytes, LKB1 inactivation nonetheless facilitates transformation of B, but not T, lymphocytes.