White Papules on the Backs of a Middle-Aged Man and His Son.

A middle-aged man came in for evaluation of "white spots" on his upper body. The number of lesions had increased progressively over the past 20 years but were asymptomatic. The patient expressed concern that his young son had recently developed similar lesions on the upper part of his back. Physical examination revealed numerous, slightly elevated, flat-topped papules scattered over the back, chest, and upper extremities (Figure 1). Each 4- to 6-mm papule was oval or round, ivory white, with a cobblestone surface. The patient's son was also examined and found to have six papules scattered across the upper part of his back and legs, identical in morphology to those of our patient. A shave biopsy was taken from of one of the papules. Results from routine hematoxylin-eosin, as well as Melan-A sections, are shown (Figure 2). The diagnosis was familial keratosis alba or familial hypochromic seborrheic keratosis.

CDK inhibitors upregulate BH3-only proteins to sensitize human myeloma cells to BH3 mimetic therapies.

BH3 mimetic drugs induce cell death by antagonizing the activity of antiapoptotic Bcl-2 family proteins. Cyclin-dependent kinase (CDK) inhibitors that function as transcriptional repressors downregulate the Bcl-2 family member Mcl-1 and increase the activity of selective BH3 mimetics that fail to target this protein. In this study, we determined whether CDK inhibitors potentiate the activity of pan-BH3 mimetics directly neutralizing Mcl-1. Specifically, we evaluated interactions between the prototypical pan-CDK inhibitor flavopiridol and the pan-BH3 mimetic obatoclax in multiple myeloma (MM) cells in which Mcl-1 is critical for survival. Coadministration of flavopiridol and obatoclax synergistically triggered apoptosis in both drug-naïve and drug-resistant MM cells. Mechanistic investigations revealed that flavopiridol inhibited Mcl-1 transcription but increased transcription of Bim and its binding to Bcl-2/Bcl-xL. Obatoclax prevented Mcl-1 recovery and caused release of Bim from Bcl-2/Bcl-xL and Mcl-1, accompanied by activation of Bax/Bak. Whether administered singly or in combination with obatoclax, flavopiridol also induced upregulation of multiple BH3-only proteins, including BimEL, BimL, Noxa, and Bik/NBK. Notably, short hairpin RNA knockdown of Bim or Noxa abrogated lethality triggered by the flavopiridol/obatoclax combination in vitro and in vivo. Together, our findings show that CDK inhibition potentiates pan-BH3 mimetic activity through a cooperative mechanism involving upregulation of BH3-only proteins with coordinate downregulation of their antiapoptotic counterparts. These findings have immediate implications for the clinical trial design of BH3 mimetic-based therapies that are presently being studied intensively for the treatment of diverse hematopoietic malignancies, including lethal multiple myeloma.