Figure 4.

Cip/Kip proteins main deregulations and functions in different hematopoietic malignancies. Schematic representation of the hematopoietic tree and main functions exerted by Cip/Kip proteins in different hematopoietic malignancies. Increased p21^Cip1/Waf levels have been reported in AML1-ETO positive AML patients, where it is believed to support LSCs maintenance and self-renewal ability. p21^Cip1/Waf anti-apoptotic functions associated with its cytoplasmatic localization have been observed in AML blasts and in cell lines derived from human CML in blast crisis. In PML-RARα LSCs, p21^Cip1/Waf expression maintains self-renewal of LSCs and limits DNA damage, thus protecting them from functional exhaustion and conferring chemoresistance. In MLL-AF10 induced AML, p21^Cip1/Waf suppression mediated by miR-17-91 leads to decreased leukemia latency. Elevated p27^Kip1 levels in B-CLL where they confer protection against apoptosis, are associated with poor outcome. In hairy cell leukemia, a form of B-CLL, CDKN1B gene encoding for p27^Kip1 is the second most common altered gene by frame shift mutations. In MM, higher miR-148a levels correlate with decreased CDKN1B expression leading to sustained proliferation. In CML, overexpression of miR-152-3p targets p27^Kip1 and promotes leukemia malignancy. In AML, p27^Kip1 is subjected to FLT3-ITD phosphorylation (pY88- p27Kip1) which mediates p27^Kip1 degradation. BCR-ABL1⁺ CML can promote degradation of nuclear p27^Kip1 and to increased cytoplasmatic p27^Kip1, thus compromising p27^Kip1 tumor suppressor activity and promoting leukemic cell survival. p57^Kip2 gene has been frequently found methylated in diffuse large B-cell lymphoma patients, where the low-risk group it is associated with a more favorable overall survival.