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Verify a Florida Driver's License Number Florida Department of Motor Vehicles. Verify Social Security Number Free SSN Validator. Verify a company's Workers Comp. Acute myeloid leukemia (AML) manifests as phenotypically and functionally diverse cells, often within the same patient. Intratumor phenotypic and functional heterogeneity have been linked primarily by physical sorting experiments, which assume that functionally distinct subpopulations can be prospectively isolated by surface phenotypes.

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Acute myeloid leukemia (AML) is a difficult to treat malignancy with heterogeneous molecular and clinical features.^1,2 Historically, AML survival rates have lagged behind other hematologic cancers, with a five-year relative overall survival rate of 27.4% compared with 68.0% in chronic myeloid leukemia or 71.0% in acute lymphocytic leukemia.³

1. The clinical and prognostic relevance of many recently identified driver gene mutations in adult acute myeloid leukemia (AML) is poorly defined. We sequenced the coding regions or hotspot areas of 68 recurrently mutated genes in a cohort of 664 patients aged 18 to 86 years treated on 2 phase 3 trials of the German AML Cooperative Group (AMLCG).
2. The inspection report carried out by AML’s driver is a visual inspection only and is not concerned with the mechanics of the vehicle All goods and valuables must, where possible, be removed from the vehicle prior to collection. If not they must be detailed on AML.

The elusiveness of durable remission after treatment may stem from the multifaceted and complex nature of blast cell populations within various subtypes of AML.^2,4 AML can be characterized based on several factors, including genetically determined prognostic risk, surface markers, or biological aberrations such as signaling pathway dysregulation.^5-7

See beyond mutation status

Identifying the molecular characteristics of AML blast populations is crucial for target-based therapy.

Emerging research has identified several clinically actionable biological aberrations, some of which are drivers of disease progression.²

The complexity of AML

Genetic ProfileAML is a heterogeneous condition with varying genetic expression within blast cell populations.⁶ Identifying patterns of molecular mutations can provide prognostic information and may help inform treatment decisions.

The complexity of AML

Surface Markers^5,8AML cells can also be characterized by protein expression, including cell surface markers such as CD33 or CD123. Ligand or receptor proteins that are preferentially expressed in leukemic blasts may be suitably targeted using antibody-based approaches.⁵

The complexity of AML

Pathway
Dysregulation^5,9,10Another characterization of AML is based on the dysregulation of signaling pathways, which may occur downstream of genetic mutations or protein overexpression. Aberrant signaling may lead to disruption in cellular processes that are normally tightly regulated, thus driving disease progression.⁵

Targeting Apoptotic Pathways
The BCL-2 family of proteins

Apoptosis, or programmed cell death, is a vital cellular process that contributes to tissue homeostasis by balancing controlled proliferation.¹¹ It is predominantly regulated by the BCL-2 family, a group of proteins that either promote or suppress the apoptotic signaling process.^11,12

BCL-2 family of proteins

Targeting Apoptotic Pathways
The BCL-2 family of proteins

The BCL-2 family proteins vary in their expression and activity but can generally be categorized into three groups.

Targeting Apoptotic Pathways
The BCL-2 family of proteins

The BCL-2 family proteins vary in their expression and activity but can generally be categorized into three groups.

Targeting Apoptotic Pathways
The BCL-2 family of proteins

The BCL-2 family proteins vary in their expression and activity but can generally be categorized into three groups.

The apoptotic cascade

Normally, all three groups of apoptotic proteins balance and regulate one another, ensuring the survival of healthy cells and the death of damaged cells.^13,15

The apoptotic cascade begins when DNA damage triggers a series of upstream responses, which are detected by the BH3-only group. BH3-only proteins are then upregulated, anti-apoptotic proteins are downregulated, and the balance between anti- and pro-apoptotic BCL-2 proteins shifts. The imbalance prompts the activation of pro-apoptotic proteins like BAK, BAX, or BOK.¹⁶

Once this occurs, one of two processes take place:

If the expression of anti-apoptotic proteins becomes dysregulated, aberrant proliferation, dedifferentiation, and other abnormal cellular processes may occur. This mechanism may be found in the pathogenesis of many hematologic malignancies, including AML¹⁶

How MCL-1 drives
AML blast survival

Myeloid cell leukemia 1, or MCL-1, is an anti-apoptotic member of the BCL-2 family.¹¹ Though similar in structure to other anti-apoptotic BCL-2 proteins, MCL-1 has specific cellular functions and affinities.^13,14

MCL-1 is essential for early embryonic development and survival of multiple cell lineages including lymphocytes, hematopoietic stem cells, neutrophils and neurons.^7,11 However, overexpression of MCL-1 may result in excessive inhibition of pro-apoptotic proteins and their sensitizers. This provides an avenue for persistent AML blast survival.^11,16

How MCL-1 drives
AML blast survival

MCL-1 constrains apoptosis in two ways:

Directly binding to and sequestering pro-apoptotic proteins like BAK or BAX, inhibiting their ability to permeabilize the mitochondrial outer membrane¹³

Binding to sensitizer proteins like NOXA, PUMA, or BAD, inhibiting their ability to activate BAK, BAX, or BOK¹³

How MCL-1 drives
AML blast survival

MCL-1 also regulates mitochondrial metabolism

Mitochondrial matrix-localized MCL-1 promotes normal mitochondrial cristae structure, as well as mitochondrial fusion. MCL-1 may also support oxidative phosphorylation, ATP production, and maintenance of mitochondrial membrane potential. These functions may also be important for promoting cancer cell survival, as showcased by the inability of cancer cells to endure the genetic deletion of MCL-1 despite the presence of other anti-apoptotic proteins. It is possible, therefore, that both the anti-apoptotic and mitochondrial functions of MCL-1 synergize to promote leukemic progression.¹¹

Defining MCL-1–dependent AML

Certain subsets of AML rely on MCL-1 for survival^14,18

MCL-1 promotion of cancer cell survival can be observed in cancer cells where a subversion of cellular checkpoints has allowed for the increased expression of anti-apoptotic proteins. These proteins 'soak up' the increased presence of pro-apoptotic proteins.¹¹ For a subset* of AML, this may be the dominant mechanism of blast survival. In other words, this subset of AML blasts is addicted to MCL-1 and may be susceptible to MCL-1–targeted therapeutic intervention.^14,18

Enabling apoptosis in
MCL-1–dependentAML blasts

Downregulating MCL-1 shifts the balance between pro- and anti-apoptotic proteins¹⁴

Given the dependence of certain AML blasts on MCL-1, a leading clinical hypothesis posits that downregulating MCL-1 may free pro-apoptotic proteins and their effectors, allowing the apoptotic cascade to be completed.¹⁴

Enabling apoptosis in
MCL-1–dependentAML blasts

MCL-1 is a short-lived protein¹³

Given the unique vulnerability of MCL-1–dependent AML, clinical efforts have been exploring ways to downregulate MCL-1.^16,19This option is attractive for two reasons.

Therefore, targeting upstream regulators is expected to reduce MCL-1 levels rapidly. One such regulator is cyclin-dependent kinase 9, or CDK9.^13,19

Targeting CDK9 may restore
apoptosis in MCL-1–dependent
AML blasts¹⁹

A potential rational treatment strategy for MCL-1–dependent AML

Targeting CDK9 may restore
apoptosis in MCL-1–dependent
AML blasts¹⁹

CDK9 as a transcription regulator

Targeting CDK9 may restore
apoptosis in MCL-1–dependent
AML blasts¹⁹

CDK9 as a transcription regulator

Targeting CDK9 may restore
apoptosis in MCL-1-dependent
AML blasts¹⁹

The mechanics of CDK9

CDK9 in cancer

CDK9 dysregulation has been observed in several malignancies

Abnormally elevated CDK9 levels are observable in many cancers. This dysregulation of downstream signaling pathways may result in the abnormal transcription profiles observed in both solid and hematologic tumors, such as^19,23:

The onco-mechanism of CDK9

CDK9 activity results in the increased expression and/or hyperactivity of oncogenes such as MCL-1 and MYC. It also promotes blast cell survival mechanisms involving anti-apoptotic factors MCL-1,BCL-2, and XIAP. This is specifically relevant to AML where upregulated MCL-1 gene expression is present in about 50% of relapsed/refractory patients.¹⁹

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A potential clinical strategy, therefore, is to regulate the expression of CDK9. Additionally, it is hypothesized that inhibition of CDK9 will prevent transcription and may reduce overall levels of mRNA, including MCL-1.¹⁹

Inhibition of CDK9 has been intriguing ever since researchers established its connection with oncogenic factors such as MYC, MCL-1, and anti-apoptotic proteins such as BCL-2 and MCL-1.¹⁹ The reasoning behind this treatment strategy is strengthened by two factors:

CDK9 targeting in AML

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MCL-1 dependency within a subset* of AML blasts provides a therapeutic target.¹⁴ The short half-life of MCL-1 means that it is susceptible to the manipulation of upstream regulators.¹³ Research has shown that CDK9 activity is crucial to maintaining the MCL-1 expression required for MCL-1–dependent AML blast survival.^19,21
Inhibition of CDK9 results in reduced levels of MCL-1, reestablishing malignant cells' ability to undergo apoptosis.^19,21 Because MCL-1 has a short half-life, the effect is expected to occur rapidly.¹³

CDK9 targeting in AML

Preliminary clinical data suggest that CDK9 inhibition may have selective activity against AML blasts, possibly due to dependence on MCL-1. Therefore, MCL-1 regulation via inhibition of CDK9 may be a rational therapeutic strategy for AML.^19,23

Assessing Compliance with BSA Regulatory Requirements

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Customer Identification Program—Overview

Objective. Assess the bank’s compliance with the statutory and regulatory requirements for the Customer Identification Program (CIP).

All banks must have a written CIP. ⁴⁰ The CIP rule implements section 326 of the USA PATRIOT Act and requires each bank to implement a written CIP that is appropriate for its size and type of business and that includes certain minimum requirements. The CIP must be incorporated into the bank’s BSA/AML compliance program, which is subject to approval by the bank’s board of directors. ⁴¹ The implementation of a CIP by subsidiaries of banks is appropriate as a matter of safety and soundness and protection from reputational risks. Domestic subsidiaries (other than functionally regulated subsidiaries subject to separate CIP rules) of banks should comply with the CIP rule that applies to the parent bank when opening an account within the meaning of 31 CFR 1020.100. ⁴²

The CIP is intended to enable the bank to form a reasonable belief that it knows the true identity of each customer. The CIP must include account opening procedures that specify the identifying information that will be obtained from each customer. It must also include reasonable and practical risk-based procedures for verifying the identity of each customer. Banks should conduct a risk assessment of their customer base and product offerings, and in determining the risks, consider:

• The types of accounts offered by the bank.
• The bank’s methods of opening accounts.
• The types of identifying information available.
• The bank’s size, location, and customer base, including types of products and services used by customers in different geographic locations.

Pursuant to the CIP rule, an 'account' is a formal banking relationship to provide or engage in services, dealings, or other financial transactions, and includes a deposit account, a transaction or asset account, a credit account, or another extension of credit. An account also includes a relationship established to provide a safe deposit box or other safekeeping services or to provide cash management, custodian, or trust services.

An account does not include:

• Products or services for which a formal banking relationship is not established with a person, such as check cashing, funds transfer, or the sale of a check or money order.
• Any account that the bank acquires. This may include single or multiple accounts as a result of a purchase of assets, acquisition, merger, or assumption of liabilities.
• Accounts opened to participate in an employee benefit plan established under the Employee Retirement Income Security Act of 1974.

The CIP rule applies to a 'customer.' A customer is a 'person' (an individual, a corporation, partnership, a trust, an estate, or any other entity recognized as a legal person) who opens a new account, an individual who opens a new account for another individual who lacks legal capacity, and an individual who opens a new account for an entity that is not a legal person (e.g., a civic club). A customer does not include a person who does not receive banking services, such as a person whose loan application is denied. ⁴³ The definition of 'customer' also does not include an existing customer as long as the bank has a reasonable belief that it knows the customer’s true identity. ⁴⁴ Excluded from the definition of customer are federally regulated banks, banks regulated by a state bank regulator, governmental entities, and publicly traded companies (as described in 31 CFR 1020.315(b)(1) through (4)).

Customer Information Required

The CIP must contain account-opening procedures detailing the identifying information that must be obtained from each customer. ⁴⁵ At a minimum, the bank must obtain the following identifying information from each customer before opening the account: ⁴⁶

• Name.
• Date of birth for individuals.
• Address. ⁴⁷
• Identification number. ⁴⁸

Based on its risk assessment, a bank may require identifying information in addition to the items above for certain customers or product lines.

Customer Verification

The CIP must contain risk-based procedures for verifying the identity of the customer within a reasonable period of time after the account is opened. The verification procedures must use 'the information obtained in accordance with [31 CFR 1020.220] paragraph (a)(2)(i),' namely the identifying information obtained by the bank. A bank need not establish the accuracy of every element of identifying information obtained, but it must verify enough information to form a reasonable belief that it knows the true identity of the customer. The bank’s procedures must describe when it will use documents, nondocumentary methods, or a combination of both.

Verification Through Documents

A bank using documentary methods to verify a customer’s identity must have procedures that set forth the minimum acceptable documentation. The CIP rule gives examples of types of documents that have long been considered primary sources of identification. The rule reflects the federal banking agencies’ expectations that banks will review an unexpired government-issued form of identification from most customers. This identification must provide evidence of a customer’s nationality or residence and bear a photograph or similar safeguard; examples include a driver’s license or passport. However, other forms of identification may be used if they enable the bank to form a reasonable belief that it knows the true identity of the customer. Nonetheless, given the availability of counterfeit and fraudulently obtained documents, a bank is encouraged to review more than a single document to ensure that it has a reasonable belief that it knows the customer’s true identity.

For a 'person' other than an individual (such as a corporation, partnership, or trust), the bank should obtain documents showing the legal existence of the entity, such as certified articles of incorporation, an unexpired government-issued business license, a partnership agreement, or a trust instrument.

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Verification Through Nondocumentary Methods

Banks are not required to use nondocumentary methods to verify a customer’s identity. However, a bank using nondocumentary methods to verify a customer’s identity must have procedures that set forth the methods the bank will use. Nondocumentary methods may include contacting a customer; independently verifying the customer’s identity through the comparison of information provided by the customer with information obtained from a consumer reporting agency, public database, or other source; checking references with other financial institutions; and obtaining a financial statement.

The bank’s nondocumentary procedures must also address the following situations: An individual is unable to present an unexpired government-issued identification document that bears a photograph or similar safeguard; the bank is not familiar with the documents presented; the account is opened without obtaining documents (e.g., the bank obtains the required information from the customer with the intent to verify it); the customer opens the account without appearing in person; or the bank is otherwise presented with circumstances that increase the risk that it will be unable to verify the true identity of a customer through documents.

Additional Verification for Certain Customers

The CIP must address situations where, based on its risk assessment of a new account opened by a customer that is not an individual, the bank will obtain information about individuals with authority or control over such accounts, including signatories, in order to verify the customer’s identity. This verification method applies only when the bank cannot verify the customer’s true identity using documentary or nondocumentary methods. For example, a bank may need to obtain information about and verify the identity of a sole proprietor or the principals in a partnership when the bank cannot otherwise satisfactorily identify the sole proprietorship or the partnership.

Lack of Verification

The CIP must also have procedures for circumstances in which the bank cannot form a reasonable belief that it knows the true identity of the customer. These procedures should describe:

• Circumstances in which the bank should not open an account.
• The terms under which a customer may use an account while the bank attempts to verify the customer’s identity.
• When the bank should close an account, after attempts to verify a customer’s identity have failed.
• When the bank should file a SAR in accordance with applicable law and regulation.

Recordkeeping and Retention Requirements

A bank’s CIP must include recordkeeping procedures. At a minimum, the bank must retain the identifying information (name, address, date of birth for an individual, TIN, and any other information required by the CIP) obtained at account opening for a period of five years after the account is closed. ⁴⁹ For credit cards, the retention period is five years after the account closes or becomes dormant. The bank must also keep a description of the following for five years after the record was made:

• Any document that was relied on to verify identity, noting the type of document, the identification number, the place of issuance, and, if any, the date of issuance and expiration date.
• The method and the results of any measures undertaken to verify identity.
• The results of any substantive discrepancy discovered when verifying identity.

Comparison With Government Lists

The CIP must include procedures for determining whether the customer appears on any federal government list of known or suspected terrorists or terrorist organizations. Banks are contacted by the U.S. Treasury in consultation with their federal banking agency when a list is issued. At such time, banks must compare customer names against the list within a reasonable time of account opening or earlier, if required by the government, and they must follow any directives that accompany the list.

As of the publication date of this manual, there are no designated government lists to verify specifically for CIP purposes. Customer comparisons to Office of Foreign Assets Control lists and 31 CFR 1010.520 (commonly referred to as section 314(a) requests) remain separate and distinct requirements.

Adequate Customer Notice

The CIP must include procedures for providing customers with adequate notice that the bank is requesting information to verify their identities. The notice must generally describe the bank’s identification requirements and be provided in a manner that is reasonably designed to allow a customer to view it or otherwise receive the notice before the account is opened. Examples include posting the notice in the lobby, on a Web site, or within loan application documents. Sample language is provided in the regulation:

IMPORTANT INFORMATION ABOUT PROCEDURES FOR OPENING A NEW ACCOUNT — To help the government fight the funding of terrorism and money laundering activities, federal law requires all financial institutions to obtain, verify, and record information that identifies each person who opens an account. What this means for you: When you open an account, we will ask for your name, address, date of birth, and other information that will allow us to identify you. We may also ask to see your driver’s license or other identifying documents.

Reliance on Another Financial Institution

A bank is permitted to rely on another financial institution (including an affiliate) to perform some or all of the elements of the CIP, if reliance is addressed in the CIP and the following criteria are met:

• The relied-upon financial institution is subject to a rule implementing the AML program requirements of 31 USC 5318(h) and is regulated by a federal functional regulator. ⁵⁰
• The customer has an account or is opening an account at the bank and at the other functionally regulated institution.
• Reliance is reasonable, under the circumstances.
• The other financial institution enters into a contract requiring it to certify annually to the bank that it has implemented its AML program, and that it will perform (or its agent will perform) the specified requirements of the bank’s CIP.

Use of Third Parties

The CIP rule does not alter a bank’s authority to use a third party, such as an agent or service provider, to perform services on its behalf. Therefore, a bank is permitted to arrange for a third party, such as a car dealer or mortgage broker, acting as its agent in connection with a loan, to verify the identity of its customer. The bank can also arrange for a third party to maintain its records. However, as with any other responsibility performed by a third party, the bank is ultimately responsible for that third party’s compliance with the requirements of the bank’s CIP. As a result, banks should establish adequate controls and review procedures for such relationships. This requirement contrasts with the reliance provision of the rule that permits the relied-upon party to take responsibility.

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Other Legal Requirements

Nothing in the CIP rule relieves a bank of its obligations under any provision of the BSA or other AML laws, rules, and regulations, particularly with respect to provisions concerning information that must be obtained, verified, or maintained in connection with any account or transaction.

The U.S. Treasury and the federal banking agencies have provided banks with Frequently Asked Questions (FAQ), which may be revised periodically. The FAQs and other related documents (e.g., the CIP rule) are available on FinCEN’s and the federal banking agencies’ Web sites.