Unveiling the complexity of CK+ AML

In acute myeloid leukemia (AML), cytogenetic abnormalities are present in more than half of patients and these chromosomal alterations are critical factors that determine response to chemotherapy and survival.^1,2 

Historically, metaphase analysis has stratified AML patients into 1 of 3 cytogenetic categories (ie, favorable, intermediate, and adverse),²  although recently a new category (monosomal karyotype [MK]), associated with dismal prognosis, has been described.^3,4  Unfortunately, the molecular mechanisms predisposing the genetic instability observed in patients with complex and monosomal karyotype have remained elusive.

TP53, the most commonly mutated tumor-suppressor gene in human cancers, is the master regulator of cell cycle, playing a major role in determining the fate of cells that contain damaged DNA. Upon DNA damage, the tumor protein p53 can delay cell-cycle progression, allowing cells to either repair their damaged DNA or initiate programmed cell death. In the absence of the normal activated p53 protein, either because of loss of tumor-suppressor function mutations and/or deletion of genetic material, cells containing damaged DNA can survive and proliferate, which contributes to malignant transformation. Although most TP53 missense mutations cause loss of p53-dependnt tumor-suppression function, hotspot mutations located at 4 codons (175, 248, 249, and 273) may also acquire gain-of-function properties to promote tumorigenesis. In fact, these gain-of-function p53 mutations have been associated with genetic instability, leading to recurrent interchromosomal translocation, and defective G2/M checkpoint through inactivation of the Mre11/ATM-dependent DNA damage responses.^5,6 

In an attempt to better understand the molecular mechanisms associated with complex chromosomal rearrangements, Rücker et al, on behalf of the German-Austrian AML Study Group (AMLSG), determined the molecular and genomic profile of TP53 in a large group of AML patients with complex karyotype and the clinical and prognostic features associated with these alterations.⁷  Their findings suggest that abnormalities in TP53 are commonly found in AML with complex and monosomal karyotype and negatively impact the outcome of these patients, independent of other variables. Using a combined approach to detect both DNA copy number abnormalities as well as the mutational status of TP53, the authors established that nearly 70% of AML patients with a complex karyotype have a biallelic inactivation of TP53.⁷  AML patients with mono- or biallelic TP53 alterations were older, which is consistent with the higher frequency of complex and monosomal karyotypes in older patients.⁴  In addition, these patients presented with unique features, such as high degree of genetic complexity and correlation with specific genetic alterations, such as 5/5q− and concomitant −5/5q− and −7/7q−. Interestingly, although a positive correlation between cytogenetically defined MK+ AML and TP53 alteration was noted (> 85% of cases), a correlation could not be established when MK was determined using more sensitive methods (DNA copy loss array data). Clinically, abnormalities in TP53 were independently associated with chemoresistance, measured by lower complete remission rates and higher rates of refractory disease, and dismal median and 3-year overall survival rates that did not seem to be improved by allogeneic hematopoietic stem cell transplantation (alloHSCT); albeit the sample size was small.

The results presented by Rücker et al are extremely significant as they begin to unveil the molecular mechanisms of leukemogenesis in AML patients with complex karyotype. However, several questions remain in light of this report. First, what are the molecular leukemogenic mechanisms in the nearly 30% of AML patients with complex karyotype and lack of TP53 alterations? A recent report suggests that amplifications of the 1q chromosome region, which contains the potent p53 inhibitor MDM4, were identified in nearly 20% of patients with leukemic transformation after chronic-phase myeloproliferative neoplasms.⁸  As expected, these amplifications were always mutually exclusive from TP53 mutations. Thus, could other downstream (ATM) or upstream (MDM2) regulators of the p53-signaling pathway also be involved? These questions have not been fully explored to date. Next, could differences in the baseline clinical characteristics, chemosensitivity, and prognosis be uncovered in patients with hotspot mutations (codons 175, 248, 249, and 273) who also have gain-of-function properties? Finally, and likely most importantly, how can the dismal outcome of these patients be improved? Nearly 90% of TP53-altered patients also had a cytogenetically defined MK+ AML, suggesting that MK may be a surrogate for TP53 abnormalities. Although an initial retrospective study conducted at the Fred Hutchinson Cancer Research Center suggested that alloHSCT might improve the dismal outcome of patients with MK+ AML,⁹  novel therapeutic approaches likely will need to be evaluated in this subset of very-high-risk patients as alloHSCT resulted in a limited survival improvement in larger subsequent analyses.¹⁰ 

In summary, abnormalities in TP53 are common in this subgroup of patients with AML and play a pivotal role on the inferior outcomes observed in these patients.